Abstract
Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood–brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging.
Keywords: animal models, cerebral blood flow, inflammation, vascular cognitive impairment
Introduction
Epidemiology of Vascular Cognitive Impairment
Dementia has an overall prevalence of 5% to 7% in ≥60-year-old people.1 After Alzheimer's disease (AD), vascular dementia is the second most common form of dementia.2 It is the most severe form of vascular cognitive impairment (VCI), which is the collection of all cognitive changes from mild cognitive impairment to dementia, caused by any cardiovascular factor.3 As the prevalence of both cardiovascular diseases (CVDs) and dementia increases with age, the rising percentage of aged people in the population will lead to a high number of cardiovascular and dementia patients in the near future. For the year 2010, 35.6 million dementia cases were estimated and this number will increase to approximately 65.7 million in 2030 and 115.4 million in 2050.1 Moreover, considering that dementia is estimated as the most burdensome neuropsychiatric disorder in elderly,4 this will lead to an enormous increase in costs and need of caregivers in the upcoming years.
Cardiovascular Disease and Cognition: Evidence in Humans
Cardiovascular diseases such as heart failure (HF), atherosclerosis, and hypertension are associated with an increased risk of cognitive impairment and dementia.5, 6, 7, 8, 9, 10, 11 One of the mechanisms by which CVD can affect cognition is by influencing the blood flow to, and in, the brain. The effects of altered cerebral hemodynamics on cognitive function have been reviewed extensively.12, 13 Cardiovascular disease may reduce cerebral blood flow (CBF), which is associated with cognitive decline.14, 15, 16 In addition to global perfusion changes, vascular autoregulation may be compromised, causing an enhanced vulnerability to hypoperfusion, as was shown in elderly people with hypertension.17 Intriguingly, improvement of heart function or blood pressure has positive effects on cognitive functioning. Clinical studies showed, e.g., that cardiac transplantation led to improved cognitive abilities.18 Similar improvements in cognitive function were obtained using cardiac resynchronization therapy or angiotensin-converting enzyme inhibitors in patients with HF.19, 20 Carotid artery stenting in patients with carotid stenosis and cognitive impairment also significantly improves cognition.21
Apart from these effects on brain function, structural brain abnormalities are also associated with CVD, including white matter lesions (WMLs), blood–brain barrier (BBB) alterations, microinfarcts, brain atrophy, and cerebral inflammation.3, 7, 22, 23 However, the causal links between these associations are largely unknown. Cerebral hypoperfusion may be an important link between CVD and cognitive decline,12 but this hypothesis is not generally accepted. Although multiple association studies have suggested a link between CBF and VCI, the evidence is still incomplete as data from prospective studies are still lacking.
Therefore, more basic research is needed to understand the mechanisms underlying these clinical observations.
Animal Research
In the dementia field, animal research has focused almost exclusively on mouse models of Alzheimer's disease, whereas only limited research has been performed on other forms of dementia. Because cerebral hypoperfusion models mostly involve surgical interventions, many studies have been performed in rats. In a few studies monkeys are used, because their brains physiologically more resemble the human brain. Nevertheless, mouse models are preferred to study the relation of CV dysfunction on cerebral perfusion and cognition, because of the plethora of genetic models available. These models allow investigation of the interactions between different risk factors and comorbidities, and dissection of the molecular mechanisms involved.
Therefore, this literature review focuses on the published cerebral data in mouse models of CVDs, selects the models suited best to study the mechanisms of VCI, and pinpoints gaps in the literature. It includes mouse models for atherosclerosis, HF, and cerebral hypoperfusion, and briefly addresses hypertension and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) models. Histologic brain changes, cerebral vascular reactivity, and functional cerebral changes will be discussed.
Search Strategy
Studies of potentially interesting mouse models were identified from PubMed with the search terms: ‘Mouse' AND ‘Brain' OR ‘Cerebral' AND ‘Atherosclerosis' OR ‘Hypertension' OR ‘Heart failure' OR ‘Perfusion' OR ‘CADASIL.' Furthermore, search terms such as ‘Cognition,' ‘Memory,' ‘MRI,' ‘CBF' in combination with ‘Mouse', and cross-references were used to increase the amount of potentially interesting models and papers. The exclusion criteria were as follows: human data; stroke data; noncerebral data; distal middle cerebral artery (MCA) occlusion models; and articles that did not contain a clear comparison with an appropriate control group.
Study Quality According to the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies Criteria
To judge the study quality and reliability of the papers, we scored all included papers according to the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) criteria. We used the criteria as described by Sena et al,24 with the exclusion of two criteria, i.e., ‘allocation concealment' and ‘use of animals with hypertension and diabetes.'24 ‘Allocation concealment' was excluded as we did not include data with treatment effects because this was beyond the scope of this review. The criterion ‘Use of animals with hypertension and diabetes' was excluded because this criterion is specific for stroke models. Definitions of the other criteria used in our review are provided in Table 1.
Table 1. The adjusted CAMARADES checklist with definitions as used for this review.
| Publication in peer-reviewed journal | Checked on the website of the journal or https://ulrichsweb.serialssolutions.com/ |
| Masked assessment of outcome | Positive when masked for genetic background or group assignment was mentioned for at least one measurement variable |
| Sample-size calculation | Positive when it was described how the sample size was determined, and which assumptions were made |
| Compliance with regulatory requirements | Positive when the experiment was approved by or in accordance with an animal experimentation or ethical committee |
| Statement conflict of interest | Positive when a ‘Conflict of interest', ‘Disclosure,' or ‘Competition of interest' was mentioned either with positive or negative outcome |
| Randomization | Positive when randomization was mentioned for surgery. ‘Not applicable' in the comparison of a genetic model with wild-type animals, unless there were different diets per group |
| Avoidance of anesthesia with intrinsic neuroprotective properties | Positive when ketamine was not used at any timepoint in the experiment except for final perfusion. ‘Not applicable' is genetic models without measurements under anesthesia |
| Control of physiologic variables | Positive if at least one variable is mentioned (temp., BP, HR) in the article or if mentioned in referred paper for operation description. ‘Not applicable' is genetic models without measurements under anesthesia |
BP, blood pressure; CAMARADES, Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies; HR, heart rate.
The amount of studies that report the study quality criteria is shown in Table 2. Publications perform poorly on (reporting) sample-size calculation, masked assessment of outcome, randomization, and statement conflict of interest. However, there are a few limitations with estimating study quality according to these criteria.
Table 2. Quality characteristics of the adjusted CAMARADES checklist for all papers included in this review.
| Model | Peer-reviewed publication | Masked assessment of outcome | Sample-size calculation | Compliance with regulatory requirements | Statement conflict of interest | Randomization of operation or sham | Avoidance of anesthetics with marked intrinsic properties | Control of physiologic variables |
|---|---|---|---|---|---|---|---|---|
| Atherosclerosis | 100% (49/49) | 39% (19/49) | 0% (0/49) | 76% (37/49) | 20% (10/49) | 50% (6/12) | 81% (13/16) | 80% (12/15) |
| ApoE−/− | 100% (35/35) | 40% (14/35) | 0% (0/35) | 66% (23/35) | 14% (5/35) | 20% (1/5) | 92% (11/12) | 73% (8/11) |
| ApoE3L | 100% (1/1) | 0% (0/1) | 0% (0/1) | 100% (1/1) | 0% (0/1) | NA | NA | NA |
| hApoB | 100% (1/1) | 0% (0/1) | 0% (0/1) | 100% (1/1) | 0% (0/1) | NA | 100% (1/1) | 100% (1/1) |
| LDLr−/− | 100% (11/11) | 45% (5/11) | 0% (0/11) | 100% (11/11) | 18% (2/11) | 71% (5/7) | 0% (0/1) | 100% (1/1) |
| LDLr−/− × hApoB | 100% (2/2) | 0% (0/2) | 0% (0/2) | 100% (2/2) | 100% (2/2) | NA | 50% (1/2) | 100% (2/2) |
| ApoB100/LDLr−/− | 100% (1/1) | 100% (1/1) | 0% (0/1) | 100% (1/1) | 100% (1/1) | NA | NA | NA |
| Heart failure | 100% (8/8) | 25% (2/8) | 0% (0/8) | 100% (8/8) | 88% (7/8) | 13% (1/8) | 25% (2/8) | 50% (4/8) |
| TAC | 100% (4/4) | 0% (0/4) | 0% (0/4) | 100% (4/4) | 75% (3/4) | 0% (0/4) | 0% (0/4) | 50% (2/4) |
| CA/CRP | 100% (2/2) | 100% (2/2) | 0% (0/2) | 100% (2/2) | 100% (2/2) | 50% (1/2) | 50% (1/2) | 100% (2/2) |
| LAD/MI | 100% (2/2) | 0% (0/2) | 0% (0/2) | 100% (2/2) | 100% (2/2) | 0% (0/2) | 50% (1/2) | 0% (0/2) |
| Hypoperfusion | 100% (17/17) | 59% (10/17) | 0% (0/17) | 88% (15/17) | 53% (9/17) | 18% (3/17) | 100% (17/17) | 76% (13/17) |
| UCCAO | 100% (5/5) | 40% (2/5) | 0% (0/5) | 100% (5/5) | 40% (2/5) | 20% (1/5) | 100% (5/5) | 40% (2/5) |
| BCAS | 100% (12/12) | 67% (8/12) | 0% (0/12) | 83% (10/12) | 58% (7/12) | 17% (2/12) | 100% (12/12) | 92% (11/12) |
| Hypertension | 100% (13/13) | 0% (0/13) | 0% (0/13) | 92% (12/13) | 15% (2/13) | 0% (0/6) | 56% (5/9) | 67% (6/9) |
| Ang II infusion | 100% (5/5) | 0% (0/5) | 0% (0/5) | 100% (5/5) | 20% (1/5) | 0% (0/5) | 40% (2/50) | 60% (3/5) |
| BPH inbred | 100% (2/2) | 0% (0/2) | 0% (0/2) | 100% (2/2) | 0% (0/2) | NA | 100% (1/1) | 100% (1/1) |
| hRNhAng-Tg | 100% (4/4) | 0% (0/4) | 0% (0/4) | 100% (4/4) | 0% (0/4) | NA | 100% (2/2) | 50% (1/2) |
| IAH CD-1 mice | 100% (1/1) | 0% (0/1) | 0% (0/1) | 100% (1/1) | 100% (1/1) | 0% (0/1) | 0% (0/1) | 100% (1/1) |
| eNOS−/− | 100% (2/2) | 0% (0/2) | 0% (0/2) | 50% (1/2) | 0% (0/2) | NA | NA | NA |
| CADASIL | 100% (6/6) | 17% (1/6) | 0% (0/6) | 100% (6/6) | 67% (4/6) | NA | 100% (2/2) | 100% (2/2) |
| Overall | 100% (93/93) | 34% (32/93) | 0% (0/93) | 84% (78/93) | 34% (32/93) | 23% (10/43) | 75% (39/52) | 73% (37/51) |
Ang, angiotensin; ApoE, apolipoprotein; BCAS, bilateral common carotid artery stenosis; BPH, benign prostatic hypertrophy; CA, cardiac arrest; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CAMARADES, Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies; CRP, cardiopulmonary resuscitation; eNOS, endothelial nitric oxide synthase; LAD, left anterior descending coronary artery; LDLr, low-density lipoprotein receptor; MI, myocardial infarction; NA, not applicable; TAC, transverse aortic constriction; UCCAO, Union des Cooperatives de Café Arabica de l'Ouest.
The colors in the table indicate the proportion of studies meeting the criterion: bold italics, <25% bold, 25% to 50% italics, 50% to 75% underlines, ≥75%. Publications perform poorly on (reporting) sample-size calculation, masked assessment of outcome, randomization, and statement conflict of interest.
A statement of conflict of interest indicated by the authors may be provided by the authors to the journal but may not have been included in the published manuscript, underestimating the study quality for these manuscripts.25
Furthermore, sample-size calculations are at least in the Netherlands a mandatory part for approval of the experiment by the ethical committee, which means these calculations have been performed for a number of these studies, although not mentioned in the manuscript. Samaranayake25 also showed that a priori sample-size calculations are underreported.
The score given to the criterion ‘avoidance of anesthesia with intrinsic neuroprotective properties' may not be relevant for our models. The value was based on the scores given to stroke papers in systematic reviews by Macleod et al.26, 27, 28 However, the score of this criterion was based on the reduction of brain infarct size by ketamine and the overestimation of treatment effect size after ketamine anesthesia in animals models of stroke. It is not known whether ketamine will have the same effect in animal models of VCI. For the VCI models, and especially the functional and perfusion measurements, the cardiovascular properties of the anesthetics may be of bigger importance for estimating outcome and treatment effect. For example, inhalation anesthetics such as isoflurane lead to vasodilation and hypotension, thus influencing the cerebral perfusion and autoregulation measurements.29 This criterion may therefore still need an adjustment for VCI models in the future and may have led to inaccurate scores for study quality in the current analysis.
The average quality per study was 51%. Five of the 93 publications scored below 25% and were excluded from this review (Supplementary Table 1).
Atherosclerosis Models
The pathology of atherosclerosis generally starts with the accumulation of oxidized low-density lipoprotein (LDL) particles in the intima of an artery, leading to an immune response, and formation and accumulation of foam cells.30 Atherosclerosis causes narrowing of vessels, thereby limiting the blood flow and reducing the capacity of the vessels to dilate. The end stage of atherosclerosis commonly leads to ischemia and infarction in the heart (myocardial infarction, MI) or brain (cerebral infarction).
Mice normally do not develop atherosclerosis. Most of the atherosclerotic mouse models are therefore based on alterations in the ApoE, ApoB, and LDLr genes. Apart from these genetic modifications, there is a difference in vulnerability between strains for developing atherosclerosis, with C57BL/6 mice being the most susceptible inbred strain.31 The C57BL/6 strain is therefore used as background for the atherogenic models and as wild-type (WT) control. As in humans, the degree of atherosclerosis in these mouse models depends on the diet, with high-fat and high-cholesterol diets leading to a faster disease progression.
Table 3 shows an overview of all cerebral changes found in atherogenic mouse models. Data of atherogenic models that are combined with other models, surgeries, or treatments with regard to the baseline model are not included in the tables.
Table 3. Structural and functional brain changes in atherosclerotic mouse models.
| Model | Findings | Age | Gender | Diet | Sample size | References |
|---|---|---|---|---|---|---|
| ApoE−/− | ||||||
| Vasculature | No difference in brain blood volume | 6–8 w | ? | Chow | N=6 | 34 |
| No difference in CBF | 8–10 w | M | ? | N=16–17 | 35 | |
| ↓ CBF | 2 w, 9 m | ? | Chow | N=4–5 | 36 | |
| ↑ BBB leakage | 2 w, 6 m | ? | Chow | N=5–6 | 36 | |
| 6–8 w | ? | Chow, WD | N=7–8 | 34 | ||
| 8–12 w | M | ? | N>30 | 41 | ||
| ±15 w, not | ? | Chow | N=9 | 39 | ||
| 31 d | ? | ? | N=3 | 38 | ||
| 6 m | M | Chow, WD (10 m) | N=4, 5 | 40 | ||
| ∼11 m, not 3 m, 14 m, not 1 m | ? | Chow vs. WD | N=7–9 | 130 | ||
| ↑ VCAM and ICAM expression | 16 w | M | Paigen, not chow | N=? | 37 | |
| No difference in vascular density | 1 m, 14 m | ? | Chow vs. WD | N=6 | 130 | |
| ↑ Internal and external diameter and CSA of cerebral arterioles | 14 w | F | Chow | N=6–9 | 131 | |
| No change in wall thickness and wall-thickness-to-lumen ratio | 14 w | F | Chow | N=6–9 | ||
| No difference in eNOS, caveolin-1, and VCAM expression | 14 w | F | Chow | N=8–16 | ||
| ↓ ACh-induced dilator response arterioles | 7–13 m | F | Chow, HFD | N=7–8 | 132 | |
| ↑ NADPH-induced dilator response arterioles | 7–13 m | F | Chow, HFD | N=7–8 | ||
| No morphologic changes arterioles | 7–13 m | F | Chow, HFD | N=7–8 | ||
| ↓ ACh-induced relaxation MCA | 16 w | M | Chow | N=5–9 | 133 | |
| ↑ Endothelin-1-induced contractile response MCA | 16 w | M | Chow | N=4–6 | ||
| No difference in L-NAME-induced contractile response MCA | 16 w | M | Chow | N=4 | ||
| Inflammation | ↑ Microglia activation and Iba-1 expression | 16w | M | Paigen, not chow | N=? | 37 |
| ↑ CD-45+ cells and leukocyte infiltration | 16 w | M | Paigen, not chow | N=? | ||
| ↑ Astrogliosis | 12 m | M | ? | N=10–14 | 51 | |
| ↑ NF-κB in pericytes | 9 m | ? | Chow | N=5–6 | 36 | |
| ↑ MMP-9 | 9 m | ? | Chow | N=5–6 | ||
| No difference in MMP-2 | 9 m | ? | Chow | N=5–6 | ||
| No difference in TNF-α mRNA | 8–16 w | M | ? | N=6 | 134 | |
| Cell/structure (de)generation | No difference in hippocampal, forebrain, or ventricle volumes | 2–5 m | M | ? | N=9 | 135 |
| ↓ Neuritic density | ≥4 m, not yet | ? | Chow | N=4–6 | 36 | |
| ↓ Pre- and postsynaptic proteins | 2 w | ? | Chow | N=4–6 | ||
| Disruption of the synaptic and dendritic organization | ≥4 m | ? | ? | N=3 | 46 | |
| No difference in synaptic or neuronal densities | 8–10 m | M | ? | N=6 | 136 | |
| ↓ Neurogenesis in SGZ of DG | 6–7 m | F | ? | N=4–6 | 42 | |
| ↑ Astrogenesis in SGZ of DG | 6–7 m | F | ? | N=4–6 | ||
| No difference in NSC numbers in SGZ of DG | 6–7 m | F | ? | N=4–6 | ||
| No difference in neuronal density | 1 m, 14 m | ? | Chow vs. WD | N=6 | 130 | |
| No defects in septohippocampal cholinergic system | 3 m, 12 m, 24 m | ? | ? | N=4–5 | 137 | |
| Neuronal function | ↓ Sensory-evoked neuronal functioning | 4 m, not 2 w | ? | Chow | N=4–6 | 36 |
| ↓ TBS-induced LTP in CA1 | 4 m, not 18 m | ? | ? | N=5 | 45 | |
| ↓ TBS-induced LTP in CA1 | 8–10 m | M | ? | N=5 | 44 | |
| ↓ Population spike amplitude in LTP | 15 m | ? | ? | N=8 | 52 | |
| Metabolism | No difference in ChAT activity in the hippocampus, parietal cortex, and striatum | 3 m, 12 m, 24 m | ? | ? | N=−5 | 137 |
| ↑ Arginase activity | 14 m, not 1 m | ? | Chow vs. WD | N=10 | 130 | |
| AD pathology | ↓ Aβ clearance | 8–10 w, 9–10 m | M | ? | N=3–4 | 53 |
| Hyperphosphorylated tau | 4 m | M | ? | N=6 | 54 | |
| ↑ Intraneuronal P-τ inclusions | ∼10 m | M+F | HCD, not chow | N=4–8 | 138 | |
| Cognition | MWM: ↓ performance | 4–5 m | M | ? | N=10–12 | 48 |
| 5–6 m | M | ? | N=10–11 | 49 | ||
| 14–16 m, not | F | ? | N=10–16 | 50 | ||
| 5–6 m | M | ? | N=5–15 | 51 | ||
| 12 m, 15 m | ? | ? | N=9 | 52 | ||
| MWM: no difference | 8–10 m | M | ? | N=12 | 136 | |
| Impaired learning in circular hole board | 7–8 m | M | ? | N=10–11 | 139 | |
| Cognition and stress | MWM: no difference in learning and memory after rat exposure stress | 5–6 m | M | ? | N=10–11 | 49 |
| MWM: ↑ learning and memory after rat exposure stress | 4–5 m | M | ? | N=8–10 | 48 | |
| Circular HB: no difference in learning after rat exposure | 7–8 m | M | ? | N=12–15 | 139 | |
| Locomotion | Rotarod: no difference (8–10 m) | 8–10 m | M | ? | N=12 | 136 |
| No difference in cumulative locomotor activity | 8–10 m | M | ? | N=12 | ||
| Neurologic | No difference in neurologic measures | 8–10 m | M | ? | N=12 | 136 |
| ApoE3L | ||||||
| Vasculature | Normal BBB function | 10 , 5 m | F | HF/HCD(9–10 m) | N=? | 40 |
| hApoB | ||||||
| Cell/structure (de)generation | ↑ Apoptotic signaling and cytoskeletal proteins | 6–7 m | M+F | Chow | N=? | 59 |
| ↑ Neuronal death | 6–7 m | M+F | Chow | N=? | ||
| ↑ Ventricle volume | 6–7 m | M+F | Chow | N=10 | ||
| No change in total brain volume | 6–7 m | M+F | Chow | N=10 | ||
| AD pathology | ↑ APP | 6–7 m | M+F | Chow | N=? | 59 |
| ↑ Amyloid plaques | 6–7 m | M+F | Chow | N=? | ||
| LDLr−/− | ||||||
| Vasculature | No BBB deficits | ∼9 w | ? | Chow | N=7–8 | 34 |
| ↑ Irregular and pathologic cerebral microvessels | ≥6 m | M | Chow, not HCD | N=5 | 65 | |
| ↑ Microvessel diameter | 12 m | M | (4–10 m) | N=6 | ||
| ↓ Microvessel length density | 12 m | M | N=6 | |||
| No change microvessel length | 6 m, 12 m | M | Chow | N=6 | ||
| ↓ Cerebral VEGF | ∼1 y | M | Chow, not | N=3 | 140 | |
| Inflammation | ↑ TNF-α, IL-1β, IL-6, iNOS, and COX2 | 6 m | ? | HF/HCD | N=6 | 66 |
| ↑ GFAP and CD45-immunoreactivity | 6 m | ? | Chow, 2 m HF/HCD | N=6 | ||
| ↑ Microglia activation in hypothalamus | ≥26 w | M | WD | N=6 | 141 | |
| Cell/structure (de)generation | ↓ Density CA1 presynaptic buttons | 11 m | M | Chow | N=3 | 67 |
| ↓ Density CA1 and DG presynaptic boutons) | ∼12 m | M | Chow | N=6–7 | 68 | |
| No change in presynaptic bouton density sensory cortex | ∼12 m | M | Chow | N=6–7 | ||
| ↓ Proliferating cells in the hippocampus | ∼12 m | M | Chow | N=6–7 | ||
| No (change in) (micro)infarcts, white matter rarefaction, ventricular enlargement, enlarged perivascular spaces, white matter atrophy, hippocampal neuronal loss, cortical granular atrophy, or cortical laminar necrosis | 3 m, 14 m | ? | Low fat | N=5–6 | 142 | |
| Metabolism | ↓ Mitochondrial electron transfer chain activity | 4 m | M | Chow, HCD vs. | N=5–6 | 61 |
| GSH depletion | 4 m | M | WT-chow | N=5–6 | ||
| ↑ Lipid peroxidation | 4 m | M | N=5–6 | |||
| ↓ AChE activity in prefrontal cortex | 3 m, 14 m | ? | Low fat | N=9–11 | 142 | |
| ↑ GPx and GR activity, GSH levels in the prefrontal cortex | 14 m, not 3 m | ? | Low fat | N=9–11 | ||
| ↓ GPx and GR activity, GSH levels in the hippocampus | 3 m, not 14 m | ? | Low fat | N=9–11 | ||
| ↑ Catalase activity in the prefrontal cortex | 14 m, not 3 m | ? | Low fat | N=6–10 | ||
| ↑ γ-GSC activity in the prefrontal cortex | 3 m, 14 m | ? | Low fat | N=6–10 | ||
| AD pathology | No difference in Aβ40 or Aβ42 | 6 m | M | Chow | N=5 | 62 |
| ↑ ApoE protein | 6 m | M | Chow | N=3–5 | ||
| ↓ ApoE RNA | 6 m | M | Chow | N=3–5 | ||
| ↑ BACE1 | 6 m | ? | Chow | N=6 | 66 | |
| Cognition | T-test: ↓ working memory | 6 m | M | Chow | N=10–13 | 67 |
| MWM: ↓ spatial memory, no learning deficit | 6 m | M | Chow | N=10–13 | ||
| MWM: ↓ memory, no learning deficit | 6 m, 5 m | M | HCD, not chow | N=12 | 69 | |
| MWM: no difference in spatial memory | 3 m, 14 m | ? | Low fat | N=8–20 | 142 | |
| Tone fear conditioning: ↓ procedural memory | 3 m, 14 m | ? | Low fat | N=8–20 | ||
| Object location task: ↓ spatial learning and memory with standard and cholesterol diet | 4 m | M | Chow | N=6–8 | 61 | |
| Water radial-arm maze: ↓ working memory | 6 m | ? | Chow | N=6 | 66 | |
| Locomotion | OF: ↑ walking time and ↑ distances | 6 m, 5 m | M | Chow, HCD | N=9–11 | 69 |
| OF: no difference in total distance and velocity | 6 m | M | Chow | N=10–13 | 67 | |
| OF: ↑ activity | 14 m | ? | Low fat | N=8–10 | 142 | |
| Anxiety | PPI/acoustic startle: no difference | 6 m, 5 m | M | HCD, LCD | N=11–12 | 69 |
| Elevated zero maze: no difference | 6 m, 5 m | M | HCD, LCD | N=8–11 | ||
| Light/dark exploration: no difference | 6 m, 5 m | M | HCD, LCD | N=12 | ||
| LDLr−/− × hApoB | ||||||
| Vasculature | ↓ CBF: basal and stimulated | 3 m, 6 m | M | Chow | N=4–6 | 73 |
| ↑ Myogenic tone | 3 m, 6 m | M | Chow | N=6–8 | ||
| ↓ Shear stress sensitivity | 3 m, 6 m | M | Chow | N=6–10 | ||
| ↓ FMD | 6 m | M | Chow | N=4–6? | ||
| ↑ Cerebral artery compliance | 3 m, 6 m | M | Chow | N=7 | 76 | |
| ↑ Incremental distensibility | 3 m, 6 m | M | Chow | N=7 | ||
| ↓ FMD | 3 m, 6 m | M | Chow | N=7 | ||
| Atherosclerotic lesions in circle of Willis and carotid arteries | 12 m | M | Chow | N=? | 73 | |
| No lesions in cerebral vessels | 3 m, 6 m | M | Chow | N=? | ||
| Inflammation | ↑ MMP-9 activity | 6 m | M | Chow | N=6 | 76 |
| No difference in MMP-2 activity | 6 m | M | Chow | N=6 | ||
| Cognition | MWM: ↓ learning capacity | 6 m | M | Chow | N=11–14 | 73 |
| ApoB100/LDLr−/− (Ldlr−/−Apobec1−/−) | ||||||
| Inflammation | ↑ Astrogliosis | 3 m, 18 m | M | Chow | N=? | 75 |
| ↑ Lipid peroxidation in the hippocampus, amygdala | 18 m | M | Chow | N=? | ||
| Cell/structure (de)generation | ↓ MAP2+ dendrites | 3 m, 18 m | M | Chow | N=? | |
| AD pathology | ↑ Aβ deposits, mainly in the hypothalamus | 3 m, 18 m | M | Chow | N=? | |
| Cognition | Integrated memory test: ↓ temporal episodic memory | 3 m, 18 m | M | Chow | N=6 | |
| Locomotion | Rotarod: ↓ fall latencies | 18 m | M | Chow | N=6–7 | |
| Grip strength test: ↓ strength | 3 m | M | Chow | N=6–8 | ||
| Open field: ↓ rearing, ↑ immobility | 3 m, 18 m | M | Chow | N=6–7 |
Aβ, amyloid β; AChE, acetylcholinesterase; AD, Alzheimer's disease; Apo, apolipoprotein; APP, amyloid precursor protein; BACE, b-APP-cleaving enzyme; BBB, blood–brain barrier; CA1, carbonic anhydrase 1; CBF, cerebral blood flow; ChAT, choline acetyltransferase; COX, cyclooxygenase; CSA, cyclosporin A; d, day; DG, dentate gyrus; EM, electron microscopy; eNOS, endothelial nitric oxide synthase; FMD, flow-mediated dilation; GFAP, glial fibrillary acidic protein; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; HB, hole board; HCD, high cholesterol diet; HF, heart failure; HFD, high-fat diet; ICAM, intercellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; LCD, low cholesterol diet; LDLr, low-density lipoprotein receptor; L-NAME, NG-nitro-L-arginine methyl ester; LTP, long-term potentiation; m, months; M, male; MAP2, microtubule-associate protein 2; MCA, middle cerebral artery; MMP, matrix metalloproteinase; MWM, Morris water maze; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; NSC, neural stem cells; OF, open field; P-tau, phosphorylated-tau; PPI, prepulse inhibition; SGZ, subgranular zone; TBS, theta-burst stimulation; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; w, weeks; WD, Western diet; WT, wild type; ↑, increase; ↓, decrease.
Differences compared with WT mice with the same diet, unless stated otherwise; N=amount of animals per group; ?=unknown.
Apolipoprotein E Knockout Mice
The ApoE−/− mouse model is the classic model of atherosclerosis. These mice start to develop severe hypercholesterolemia and atherosclerotic lesions in the aorta and pulmonary, coronary, and carotid arteries at the age of 8 or 10 weeks, depending on the type of diet.32, 33 The cardiovascular features of this model have been researched extensively, yet only a few studies investigated cerebral perfusion in ApoE−/− mice.
Cerebral Perfusion
In young mice (6 to 8 weeks), the cerebral blood volume of the total brain and the CBF were equal in ApoE−/− mice and controls.34, 35 In a different study, regional CBF was already reduced at 2 weeks of age and decreased progressively.36
Inflammatory Response
ApoE−/− mice fed a high-fat/high-cholate diet (Paigen) for 8 weeks showed significantly increased intracerebral expression of the vascular adhesion molecules intercellular adhesion molecule and vascular cell adhesion molecule (VCAM), which are markers for endothelial activation.37 In the brain, VCAM was mainly localized on the large- and medium-sized vessels in the cerebral cortex, striatum, thalamus, and hippocampus. Lipid deposits were found in the vessel walls, and were accompanied by leukocyte recruitment and microglial activation, the brain's main active immune defense. This immune response was found partly in the same brain regions that show endothelial activation: the cerebral cortex, striatum, hypothalamus, periventricular areas, and meninges.37 Chow-fed ApoE−/− mice, and chow- or Paigen-fed WT mice did not show microglial activation.
Blood–Brain Barrier
The BBB is probably the most studied part of the brain in ApoE−/− mice. Compared with WT mice, more spontaneous leakage is seen from 2 weeks of age, which is worse after a Western diet.34, 36, 38, 39, 40, 41 Recently, a mechanism has been proposed in which the increased BBB leakage is postulated to be because of a direct loss of the inhibitory effect of ApoE on the activation of the proinflammatory cyclophilin A (CypA)–nuclear factor-κB–matrix metalloproteinase-9 (MMP9) pathway.36 Deletion of the CypA gene Ppia in ApoE−/− mice normalized the CBF reductions, BBB integrity, and levels of NK-κB and MMP9. In this mouse model, Bell et al36 showed that the degeneration of the microvessels and reductions in microvascular length were correlated with the degree of BBB breakdown and CBF reduction and preceded neuronal and synaptic changes.
Synaptic and Dendritic Organization
Deficiency of ApoE leads to several cellular and molecular changes in the hippocampus, one of the most important regions for (spatial) memory formation. Apolipoprotein E−/− mice exhibited decreased neurogenesis in the subgranular zone of the dentate gyrus, and an increase of astrogenesis.42 These changes may be explained by the direct effects of ApoE on neural progenitor cells.43 However, the number and proliferation of neural stem/progenitor cells and the number of GABAergic interneurons were not affected.42 Intriguingly, synaptic plasticity in the hippocampus was affected in 4- to 10-month-old mice, but not in 18-month-old ApoE−/− mice.44, 45
The synaptic and dendritic organization was disrupted in ApoE-deficient mice in both the limbic system and neocortex.46 As ApoE−/− mice age, presynaptic terminals and neuronal dendrites were lost faster in the hippocampus and cortex compared with WT mice, and hippocampal neurofilament-positive axons were also more disrupted.47
Cognitive and Behavioral Changes
Apolipoprotein E-deficient mice have spatial memory impairment compared with WT during the Morris water maze (MWM) test.48, 49, 50, 51, 52 Surprisingly, under stress learning and memory of ApoE−/− mice improves, reducing their latencies and switching to a goal-directed search strategy, performing similar or even better than control mice.48, 49 This finding is attributed to ApoE genotype-related differences in the regulation of corticosterone levels and expression of cell adhesion molecules.49
Relation to Alzheimer's Disease
Apolipoprotein E-deficient mice show several hallmarks of AD, such as a reduced clearance of amyloid β (Aβ)53 and the presence of hyperphosphorylated tau.54 However, cross-breeding of ApoE−/− mice with different AD mouse models (5XFAD, PDAPP) resulted in a decrease in the amount of amyloid plaques without any effect on the inflammatory response.55, 56 Neurodegeneration has not been studied in these models.
In summary, ApoE−/− mice exhibit increased inflammation, increased BBB permeability, microvessel degeneration, reduction of neurogenesis and synapses, and cognitive impairment (see Table 3). The cerebral changes are mostly increased or accelerated when the animals are fed a high-fat diet. There are no studies investigating CBF in combination with cellular or molecular changes in normal ApoE−/− mice. Therefore, it remains unclear whether these changes are the result of atherosclerosis-induced CBF reduction or the direct effects of the lack of ApoE.
Human Apolipoprotein B
Apolipoprotein B, which is part of lipoproteins, LDL, and chylomicrons, has an important role in cholesterol transport. Human ApoB transgenic mice have shown extensive aortic atherosclerotic lesions and a reduction of approximately 25% in aortic blood flow after 18 weeks on a high-fat diet.57, 58 These effects were not present when fed a chow diet, possibly because triglyceride levels were elevated with both diets, cholesterol was only elevated when the mice were fed a high-fat diet.58, 59
Nevertheless, also on a chow diet, ApoB transgenic animals showed an increase in apoptotic signaling proteins and cytoskeletal proteins in the brain at the age of 6 to 7 months.59 In addition, extensive neuronal death and amyloid plaques were detected in the hippocampus, cerebral cortex, and hypothalamus.
With magnetic resonance imaging (MRI), an enlargement of the cerebral ventricles has been found in these mice, irrespective of diet, which was proportional to the elevated human ApoB100 levels.59 As yet, there are no data available on cerebral perfusion, BBB integrity, inflammation, or cognition for these mice.
Low-Density Lipoprotein Receptor Knockout Mice
The LDLr−/− mouse model is a commonly used model for atherosclerosis. Mutations in the LDLr gene cause familial hypercholesterolemia in humans.60 On a normal diet, the LDLr−/− mice slowly develop atherosclerosis over time; as for the other models, this process is accelerated with a high-fat diet. These mice have increased plasma cholesterol levels with both standard and fat diets, but the cholesterol level in cholesterol-enriched fed mice is threefold higher than on a standard diet.61 However, despite the elevated plasma cholesterol, the brain cholesterol does not differ between LDLr−/− mice and WT mice, irrespective of the diet.62, 63, 64
Cerebral Blood Flow, Blood–Brain Barrier, and Brain Vasculature
The effect of LDLr−/− on CBF is not yet known. In contrast to ApoE−/− mice, young LDLr knockout mice (9 weeks old) did not show BBB deficits.34 At the age of 6 to 12 months, LDLr−/− mice showed more pathologic changes in the central nervous system microvessels than WT when fed with a normal chow diet, including an overall increased diameter, a mixture of thin and irregular, as well as enlarged microvessels, very thin ‘string like' vessels, and vessels with a kinked or twisted morphology.65 These changes were more apparent in older mice.
Inflammatory Response and Synaptic and Dendritic Organization
Hippocampal levels of cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6) and proinflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase2) were increased in LDLr−/− mice compared with WT mice on a chow diet at the age of 6 months.66 The levels were not further increased by a high-fat diet. Increased activation of astrocytes (glial fibrillary acidic protein (GFAP)+) and microglia (CD45+) has been described in LDLr−/− mice.66
Low-density lipoprotein receptor−/− mice exhibited impaired mitochondrial electron transfer chain activity in the cerebral cortex, which showed an inverse correlation with blood cholesterol levels.61 They also showed glutathione depletion, changes in peroxide-removing-related enzymes (such as glutathione peroxidase (GPx) and glutathione reductase (GR)), and increased lipid peroxidation.61 Low-density lipoprotein receptor−/− mice also had a decreased density of presynaptic terminals in carbonic anhydrase 1 (CA1) and dentate gyrus,67, 68 suggesting reduced synaptic plasticity.
Cognitive and Behavioral Changes
As expected from the cellular changes in the hippocampus, LDLr−/− mice showed spatial learning and memory impairments in the object location task when fed with a normal diet as well as a cholesterol-enriched diet.61 In the Morris water maze test, LDLr-deficient mice showed impaired spatial memory with standard diet,67 whereas another study only observed impaired memory in LDLr-deficient mice on a high-fat diet around the age of 6 months.69 Also in working memory tests, such as the T-test or water radial-arm maze, LDLr-deficient mice showed poorer performances.66, 67
Studies on locomotor activity in LDLr-deficient mice have shown inconsistent results. In one study, LDLr-deficient mice showed increased locomotor activity compared with WT mice in the open field,69 whereas in an earlier study, no differences were observed.67
Low-density lipoprotein receptor-deficient mice did not have increased anxiety as shown by prepulse inhibition tests, acoustic startle reflex, the elevated zero maze, and light/dark exploration.69 High-cholesterol-fed mice showed increased anxiety during light/dark exploration, but this was true for both WT and LDLr-deficient mice.
Relation to Alzheimer's disease
As in AD pathology, ApoE total RNA levels were decreased in LDLr−/− mice, whereas ApoE protein levels were increased, both irrespective of the type of diet.62, 70 Low-density lipoprotein receptor −/− mice did not show any difference in brain Aβ40, Aβ42, or Aβ40/42 ratio with chow, high-fat, or high-cholesterol diet.62 There was no correlation between plasma cholesterol levels and cerebral Aβ40 or Aβ42.
To investigate the effect of cholesterol levels or specific LDLr function in mice on AD like pathology, LDLr-deficient mice have been backcrossed with different AD mouse models. Results of these studies are conflicting, showing either no effect or increased amyloid plaque deposition.55, 70, 71
In AD mouse models, LDLr deficiency influences memory deficits. At 13 months of age, the spatial memory performance in the MWM was further decreased in the amyloid precursor protein (APP)-overexpressing Tg2576 mouse when cross-bred with LDLr−/−.71 This effect was not yet present at 10 months of age. The MWM performance at 13 months positively correlated with the cerebral amyloid load.71
Similar to ApoE−/− mice, LDLr−/− mice show increased inflammation, microvessel abnormalities, reduction of synapses, and cognitive impairment.65, 66, 67, 69 However, no increased BBB permeability has been observed in young LDLr−/− mice (maximum 9 weeks),34 although older mice have not been studied.
Low-Density Lipoprotein Receptor−/− × Apolipoprotein B
Cerebral effects have been explored in two mouse models that combine the effect of LDLr knockout and increased ApoB expression. The first model expresses human ApoB in combination with LDLr knockout and is called LDLr−/− × hApoB, LDLR−/− Tg(ApoB+/+), or ATX.72, 73 The second model is the LDLr−/− with Apobec1−/− knockout and is called LDLr−/−Apobec1−/− or ApoB100/LDLr−/−.74, 75 Apobec1 is an enzyme in the mouse liver that edits the mRNA of ApoB, creating the truncated ApoB48. By knocking out this enzyme, the concentration of the full-length ApoB100 will increase. Both models are used as model for human familial hypercholesterolemia. These mice have increased levels of cholesterol, LDL, and triglycerides, and show atherosclerotic lesions on a normal standard diet.73, 75
Low-Density Lipoprotein Receptor−/− × Human Apolipoprotein B
Although the LDLr−/− × hApoB mice have atherosclerotic lesions in the aorta and carotid arteries after 6 months, no lesions have been observed in the large cerebral vessels at these time points. It is however described (but not shown) that LDLr−/− × hApoB mice at the age of 12 months have macroscopic atherosclerotic lesions at the bifurcations in the circle of Willis.73 The cholesterol and fatty acid content in the cerebral arteries were similar to WT mice at 3 and 6 months of age.76 In addition to atherosclerosis, LDLr−/− × hApoB mice were hypertensive at 3 and 6 months of age.73, 76
In ATX mice, different aspects of vascular reactivity have been measured in vitro and in vivo. In vivo, baseline CBF in the somatosensory cortex was reduced.73 The ex vivo measured myogenic tone was higher in cerebral arteries of ATX mice compared with WT and increased with age. Endothelial dysfunction was apparent from a reduced dilatory response to acetylcholine, lower sensitivity to wall shear stress, and lower flow-mediated dilatation, which was not affected by the nitric oxide synthase inhibitor Nω-nitro-L-arginine.73 As expected, CBF was correlated to the degree of flow-mediated dilatation. At least part of the endothelial dysfunction appeared to be due to oxidative stress, as long-term treatment with the antioxidant catechin improved most of the above responses. Contrary to the carotid arteries, the cerebral artery compliance actually increased in ATX mice with age. A possible mechanistic explanation for this finding is that MMP-9 (although not MMP-2) activity was increased in the cerebral vessels of 6-month-old mice, without changes in the cerebrovascular wall lipid composition, which typically contribute to arterial stiffness.76
These data suggest that atherogenic mouse models affect CBF and endothelial function in cerebral arteries, possibly without overt atherosclerotic lesions in the cerebral vessels. Furthermore, as shown below, this might also influence cognitive function in these mice. A direct casual link is however not provided.
Apolipoprotein B100/Low-Density Lipoprotein Receptor−/−
Little is known about the neuropathology of ApoB100/LDLr−/− mice. Although mature aortic atherosclerotic lesions have been reported in old animals, it has not been described whether these mice also have intracranial lesions. Histologically, astrogliosis has been detected in the hippocampus, amygdala, and several cortical areas. These mice also showed a reduction of microtubule-associate protein 2+ dendrites, which was age dependent in the hippocampus, but only genotype dependent in the lateral entorhinal cortex and amygdaloidal basal nucleus.75 The microtubule-associate protein 2 reduction indicates neuritic dystrophy and may contribute to the cognitive decline discussed below.
Cognitive and Behavioral Changes
At the age of 6 months, LDLr−/− × hApoB mice have a decreased learning capacity in the MWM test compared with 3-month-old LDLr−/− × hApoB mice, whereas catechin improved learning capacity.73 However, the escape latency and thus memory formation was not affected in 6-month-old LDLr−/− × hApoB mice compared with WT or 3-month-old LDLr−/− × hApoB mice.
The ApoB100/LDLr−/− transgenic mice showed impaired temporal episodic memory as tested with the integrated memory test.75 Spatial memory was not impaired compared with WT mice, but did decrease with age in both strains.
Interpretation of cognitive tests in these animals should be performed with care as the mice also had locomotor deficits, shown by shorter fall latencies in the rotarod test, reduced strength in the grip strength test, and reduction of rearing and increase of immobility in the open field.75
Relation to Alzheimer's disease
As early as at 3 months of age, vascular Aβ deposits have been observed in the ApoB100/LDLr−/mouse, followed by deposits in the hypothalamus and cortical areas at 18 months.75
All atherosclerotic mouse models that are discussed above have increased cholesterol levels when fed a high-fat diet and exhibit atherosclerotic lesions in at least the aorta. Before the age of 12 months, no lesions were reported in the brain in any of the models, although cerebral changes and cognitive impairment are already found in younger animals. This suggests that there is no direct link between the extent of intracranial atherosclerosis and cognitive function. Yet, the kind of pathologic changes reported in each model differ a lot. Most models show an increase in inflammatory response, although this has not been tested for hApoB-knock-in mice (see Table 3). Effects of atherosclerosis or the specific genes involved in endothelial function and neurodegeneration have barely been tested, although endothelial dysfunction and decreased amount or function of neurons is suspected from the sparse results available. Cerebral perfusion is only tested in ApoE−/− mice.
The effects on BBB permeability and Aβ deposition are not consistent between the different models. Most likely, the found effects are not only related to cerebrovascular dysfunction but also to a direct effect of the gene in question on the pathways involved in BBB integrity or Aβ homeostasis. It is known, e.g., that ApoE can bind to Aβ and thereby increases Aβ deposition.77, 78 Therefore, it will be essential to investigate other (nongenetic) mouse models to unravel the mechanisms involved.
Heart Failure Models
In humans, reduced cardiac output is associated with reduced cerebral perfusion, brain abnormalities, and cognitive impairment. There are several models of HF in mice, ranging from acute to chronic models and genetic to surgery-induced models. There is however no data on the cerebral effects in genetic models. Examples of surgery-induced models are the aortic constriction, cardiac arrest, and MI models (see Table 4).
Table 4. Structural and functional brain changes in heart failure mouse models.
| Model | Findings | Age at start | After operation | Gender | Sample size | References | |
|---|---|---|---|---|---|---|---|
| TAC1 | |||||||
| Vasculature | ↓ Cerebral perfusion LH | 12–15 w | 1 d, 7 d | M | N=5 | 79 | |
| ↑ Cerebral perfusion RH | 12–15 w | 1 d, 7 d | M | N=5 | 85 | ||
| ↓ RH and LH CBV | 12–15 w | 3 w, 8 w | M | N=5 | |||
| ↑ BBB albumin permeability in the hippocampus+cortex, not the striatum | 12–15 w | 1 d, 7 d | M | N=7 | 79 | ||
| Inflammation | ↑ RAGE in the hippocampus and cortex | 8–12 w | 4 h–6 w | M | N=4 | 86 | |
| ↑ Superoxide production in the hippocampus+cortex, | 12–15 w | 1 d, 7 d | M | N=9 | 79 | ||
| not the striatum | 12–15 w | 1 d LH+RH, | M | N=5 | |||
| ↑ NAD(P)H oxidase activity | 12–15 w | 7 d RH | M | N=4–6 | |||
| ↑ IL-1β and TNF-α hippocampal mRNA | 12–15 w | 1 d, 7 d | M | N=5 | |||
| ↑ GFAP+ cells | 12–15 w | 1 d, 7 d | M | N=? | |||
| No leukocyte recruitment | 1 d, 7 d | ||||||
| ↑ CD68 and Iba-1 | 12–15 w | 1 d, 3 w, 8 w | M | N=4 | 85 | ||
| ↑ IL-1β and IL-10 | 12–15 w | 3 w, not 8 w | M | N=4 | |||
| ↑ IL-1α and TGF-β | 12–15 w | 8 w, not 3 w | M | N=4 | |||
| No change in TNF-α | 12–15 w | 3 w, 8 w | M | N=4 | |||
| Cell/structure (de)generation | No difference in neuronal death | 12–15 w | 3 w, 8 w | M | N=? | 85 | |
| Metabolism | ↓ GLUT-1 in the hippocampus and cortex | 12–15 w | 3 w, 8 w | M | N=4 | ||
| ↓ 15-F2t-IsoP in the hippocampus and cortex | 12–15 w | 3 w, 8 w | M | N=6–8 | |||
| Normal GLUT-3 expression | 12–15 w | 3 w, 8 w | M | N=4 | |||
| AD pathology | ↑ Aβ deposits | 12–15 w | 8 w, not 3 w | M | N=? | 85 | |
| 8–12 w | ? | M | N=5 | 86 | |||
| Cognition | MWM: ↓ spatial memory, no change learning phase | 8–12 w | ? | M | N=? | 86 | |
| NOR: ↓ recognition memory, no change learning phase | 8–12 w | ? | M | N=? | |||
| TAC2 | |||||||
| Vasculature | ↑ BBB albumin permeability in the hippocampus and cortex | 12–15 w | 28 d | M | N=5–10 | 80 | |
| AD pathology | ↑ Aβ immunopositivity in the hippocampus and cortex | 12–15 w | 28 d | M | N=5 | ||
| CA/CRP | |||||||
| Inflammation | ↑ MMP-9 activity | 2–3 m | 1 d | M | N=4 | 123 | |
| ↑ Microglial response the hippocampus | (23–30 g) | 7 d | M | N=10–12? | 143 | ||
| Cell/structure (de)generation | ↑ Degenerated neurons in the hippocampus | (23–30 g) | 7 d | M | N=10–12? | 143 | |
| Locomotion | ↑ Overall locomotor home cage activity | (23–30 g) | 1–7 d | M | N=10–12? | ||
| LAD/MI | |||||||
| Vasculature | ↓ CBF (global, cortical and subcortical) | 2–3 m | 4–6 w | M | N=14–16 | 88 | |
| ↑ Resting tone and MT (proximal PCA) | 2–3 m | 4–6 w | M | N=6–14 | |||
| No difference in passive external diameter (proximal PCA) | 2–3 m | 4–6 w | M | N=6–14 | |||
| Inflammation | ↑ TNF-α (in PCAs) | 2–3 m | 4–6 w | M | N=4 | ||
| Cell/structure (de)generation | No difference in brain size or shape | 2–3 m | 6 w | M | N=4 | ||
| ↑ BDNF expression | 12–14 w | 2 w | M | N=4 | 144 | ||
| Cognition | MWM: no difference | 2–3 m | 6 w | M | N=4 | 88 | |
Aβ, amyloid β; AD, Alzheimer's disease; BBB, blood–brain barrier; BDNF, brain-derived natriuretic factor; CA/CRP, cardiac arrest/cardiopulmonary resuscitation; CA, carbonic anhydrase; CBV, cerebral blood velocity; d, day; GFAP, glial fibrillary acidic protein; GLUT, glucose transporter; IL, interleukin; LAD, left anterior descending coronary artery; LH, left hemisphere; m, months; M, male; MI, myocardial infraction; MMP, matrix metalloproteinase; MT, myogenic tone; MWM, Morris water maze; NADPH, nicotinamide adenine dinucleotide phosphate; NOR, novel object recognition test; RH, right hemisphere; PCA, posterior cerebral artery; RAGE, receptor for advanced glycation end products; TGF, transforming growth factor; TNF, tumor necrosis factor; w, weeks; WT, wild type; ↑, increase; ↓, decrease.
Differences compared with sham WT mice; (), weeks after surgery; N=amount of animals per group; ?=unknown.
Transverse Aortic Constriction
The transverse aortic constriction (TAC) model is a mouse model of hypertension and chronic HF. The constriction is effected by partial ligation of the aortic arch, usually between both carotid arteries (see Figure 1; TAC1 in Table 4),79 but alternatively downstream of both carotids (TAC2 in Table 4).80 Because the ligation between the carotids (TAC1) is the most commonly applied model, we will discuss this type of ligation in more detail.
Figure 1.
Most commonly used models for atherosclerosis, heart failure, and hypoperfusion to study the effect of cardiovascular risk factors on the brain. ApoE, apolipoprotein; BCAS, bilateral common carotid artery stenosis; BP, blood pressure; CBF, cerebral blood flow; TAC, transverse aortic constriction.
Transverse aortic constriction surgery induces hypertension, left ventricular hypertrophy, and cardiac failure with an acutely decreased left ventricular ejection fraction, but a preserved left ventricular ejection fraction in the long term.81, 82 Transverse aortic constriction mice have shown an increase in right carotid blood flow and peak velocity from days 1 to 28.83, 84 During this time window, the left carotid peak velocity was decreased, although the blood flow was only reduced until day 7 and returned to baseline after 14 days.83 One day after surgery, the blood pressure in the right carotid was approximately two times as high as in the left carotid,79 but no data are available on the long-term effect of TAC on the blood pressure.
Cerebral Perfusion and Blood–Brain Barrier
Transverse aortic constriction mice developed acute right hemisphere hypertension with increased cerebral perfusion in the right hemisphere, whereas the perfusion was reduced in the left hemisphere compared with sham-operated mice at days 1 and 7.79 At 3 or 8 weeks after surgery, the cerebral blood velocity was reduced in both hemispheres.85 Blood–brain barrier permeability was increased at days 1 and 7 after surgery to the same extent in both hemispheres despite the perfusion differences.79
Inflammatory Response
In the first week after the surgery, an increase in superoxide production, nicotinamide adenine dinucleotide phosphate oxidase activity, IL-1β, and TNF-α mRNA expression and GFAP+ cells was observed in the cortex and hippocampus of both hemispheres.79 This shows that hyper- and hypoperfusion may induce a similar cerebral inflammatory response.
Microglia were already activated at day 1 after TAC, and activation persists for at least 8 weeks along with increased cytokine levels.79, 85
Three and 8 weeks after ligation, the mice showed decreased glucose transporter-1 expression, whereas glucose transporter-3 levels remained normal, indicating an imbalance in glucose supply to the brain.85 Despite the perfusion differences and the inflammatory response, neuronal death was not significantly increased after 3 or 8 weeks.85
Relation to Alzheimer's disease
After 8 weeks, but not at 3 weeks, Aβ deposits were visible. The microglial marker CD11b colocalized with Aβ in the proximity of blood vessels, but not in the parenchyma.85
The cerebral amyloid deposition in the cortex and hippocampus can be influenced by receptor for advanced glycation end products (RAGE).86 As early as 4 hours after TAC, RAGE mRNA and protein levels were upregulated, most prominently in the brain vessels. This increase was still present after 6 weeks in both the hippocampus and cortex. RAGE inhibition by knockout or pharmacological means and antioxidant treatment (Tiron) reduced parenchymal Aβ deposits.86
Cognitive and Behavioral Changes
Only one recent study investigated the effect of TAC on cognition. This study showed that TAC mice manifest cognitive impairment in the (spatial) memory domain in the MWM test and novel object recognition test.86 RAGE knockout and pharmacological inhibition of RAGE, AGE, or oxidants all protected against cognitive impairment. This observation suggests that oxidative stress may have a crucial role in inducing cognitive dysfunction. The effect of RAGE inhibition on cognition has also been shown in the APPsw/0 Alzheimer mouse model.87
Myocardial Infarction
Only two studies have described the cerebral effects after MI. Myocardial infarction was induced by permanent ligation of the left anterior descending coronary artery, resulting in a reduction of CBF after 4 to 6 weeks.88 The resting and myogenic tone measured in proximal posterior cerebral arteries (PCAs) was increased ex vivo. Tumor necrosis factor-α expression was upregulated in the PCAs, localized to smooth muscle cells. This study suggests that the TNF-α–sphingosine 1)–sphingosine-1-phosphate pathway has an important role in regulating the vascular tone.
Six weeks after ligation, the mice did not have a spatial memory deficit.88
These studies suggest that HF models such as TAC and MI lead to a reduced CBF. Both models did not show (extensive) neurodegeneration in the relatively short period studied. Increased inflammation is observed in all models; however, only vascular inflammation was investigated in the MI model. Inflammation appears to have a crucial role in the pathology of these mice, as the reduction of specific inflammatory factors normalizes CBF, vascular tone, Aβ deposition, and cognition.
Cerebral Hypoperfusion Models
To study directly the effect of a reduced blood flow to the brain, hypoperfusion models can be used. In these models, either one or both carotid arteries are occluded or ligated. The degree of hypoperfusion and cerebral changes depend on the number of carotids that are ligated and the degree of ligation (see Table 5).
Table 5. Structural and functional brain changes in hypoperfusion mouse models.
| Model | Findings | Age at start | After operation | M/F | Sample size | References | |
|---|---|---|---|---|---|---|---|
| Unilateral common carotid artery occlusion | |||||||
| Vasculature | ↓ Ipsilateral CBF | 12 w; 10–11 m | 2 h–28 d | M | N=8/15 | 145 | |
| 7 d | F | N=? | 146 | ||||
| ↑ IL-1β | 12–16 w | 28 d | M | N=50 | 147 | ||
| ↑ IL-6 | |||||||
| ↓ IL-4 | |||||||
| ↓ IL-10 | |||||||
| No change in TNF-α levels↓ Cortical perfusion | |||||||
| No BBB leakage | 10–11 m | 7 d | F | N=? | 146 | ||
| Inflammation | ↑ Activated microglia | 12 w | 4 w | M | N=6 | 145 | |
| 12 w | 1 d+3 d | M | N=4 | ||||
| 12 w | 2 h+2 m | M | N=4 | ||||
| 12 w | 1 d+3 d | M | N=4 | ||||
| 12 w | 1 d | M | N=4 | ||||
| 12 w | 2 h–2 m | M | N=4 | ||||
| ↑ Activated astrocytes (GFAP) (37 d) | 8 w | 37 d | M | N=8 | 148 | ||
| ↑ Activated microglia (Iba-1) (37 d) | 8 w | 37 d | M | N=8 | |||
| ↑ ROS production in the CC and cortex | 8 w | 1 d, 37 d | M | N=6 | |||
| and striatum, | 8 w | 37 d | M | N=6 | |||
| no difference in the hippocampus | 8 w | 1 d, 37 d | M | N=6 | |||
| Cell/structure (de)generation | No WML | 14–15 m | 7 d | F | N=? | 146 | |
| WML in ipsilateral corpus callosum (4 w) | 12 w | 30 d | M | N=6 | 145 | ||
| No ischemic damage with >40% microperfusion | 12–16 w | 28 d | M | N=44 | 147 | ||
| Infarctions and neuronal damage with <35% microperfusion | M | N=3 of 6 | |||||
| No noticeable neuronal death | 4 m | 3 d, 6 w | M | N=17–21 | 149 | ||
| No necrosis or neuronal death | 10–11 m, 14–15 m | 7 d, 8 w | F | N=? | 146 | ||
| ↓ MBP in CC | 8 w | 37 d | M | N=8 | 148 | ||
| No obvious neuronal loss or morphologic changes | 8 w | 37 d | M | N=8 | |||
| Metabolism | ↓ Uptake 18F-FDG | 14–15 m | 8–16 w | F | N=? | 146 | |
| Cognition | T-maze: no difference in memory | 1 2w, 4 m | 4 w | M | N=10–20 | 145 | |
| 5 w | M | N=17–21 | 149 | ||||
| ORT: ↓ nonspatial memory | 12 w | 4 w | M | N=5–7 | 145 | ||
| 8 w | 4 w | M | N=8–14 | 146 | |||
| 14–15 m | 6 w | F | N=? | 148 | |||
| PA: ↓ fear memory | 8 w | 4 w | M | N=8–14 | 148 | ||
| MWM: no difference | 14–15 m | 6 w | F | N=? | 146 | ||
| MWM: ↑ escape latency in acquisition phase | 8 w | 5 w | M | N=8–14 | 148 | ||
| MWM: no difference in escape latency in probe trial | 8 w | 5 w | M | N=8–14 | |||
| Locomotion | OF: no difference in motor activity | 12 w | 4 w | M | N=5 | 145 | |
| Rotarod: no difference in motor function | 4 m | 6 w | M | N=17–21 | 149 | ||
| Paw grip endurance test: no difference | 10–11 m | 7 d | F | N=? | 146 | ||
| BCAS (0.18 mm) | |||||||
| Vasculature | ↓ Basal CBF | 16 w | 2 h–3 m | M | N=5–6 | 89 | |
| 10 w | 2 h–14 d, not | M | N=7–11 | 90 | |||
| 10–12 w | 30 d | M | N=24 total? | 91 | |||
| ?(20–25 g) | 1–30 d | M | N=3 | 92 | |||
| 2 h–30 d | |||||||
| ↑ BBB permeability in the white matter | ?(20–25 g) | 3 d, 14 d | M | N=4 | 92 | ||
| ↑ Capillary density in the cortex | ?(22–26 g)? | 30 d, not 1 d | M | N=4–6 | 93 | ||
| ↑ VEGF and P-eNOS | (22–26 g) | 1 d | M | N=4 | |||
| No difference in capillary density | 10–12 w | 7 d | M | N=4–6 | 98 | ||
| No difference in the diameters leptomeningeal anastomoses or vessels of the circle of Willis | 10–12 w | 7 d | M | N=4–6 | |||
| Inflammation | ↑ Activated microglia (Iba-1/MHC II) and astroglia (GFAP) | ?(20–25 g) | 4 d | M | N=6 | 92 | |
| 30 d | M | N=4? | 93 | ||||
| ?(22–26 g) | 1–2 m | M | N=37–49? | 95 | |||
| 3–4 m | 3 w | M | N=9 | 97 | |||
| 11 w | 28 d | M | N=4–8 | 98 | |||
| 10–12 w | |||||||
| ↑ Activated microglia (Iba-1/MHC II) and | 10 w | 7 d–30 d, not 3 d | M | N=28? | 90 | ||
| ↑ Astroglia (GFAP) | 10 w | 14–30 d,not 3–7 d | M | N=28? | |||
| ↑ Activated microglia (Cd11b), astroglia (GFAP), TNF-α, IL-1β, IL-6 in WM | 10 w | 14–30 d, not 7 d | M | N=5–6 | 94 | ||
| 10 w | 14–30 d, not 7 d | M | N=5–6 | ||||
| ↑ Cerebral hypoxia (hypoxyprobe) | 11 w | 3 w | M | N=8–13 | 97 | ||
| ↑ Cerebral nitrotyrosine | 11 w | 3 w | M | N=4–6 | |||
| ↑ NADPH oxidase activity, p67phox | 11 w | 3 w | M | N=4–5 | |||
| ↑ Monocyte chemoattractant protein 1, TNF-α | 11 w | 3 w | M | N=12–15 | |||
| No change SOD, eNOS | 11 w | 3 w | M | N=12–15 | |||
| ↑ MMP-2-immunoreactive glial cells | ?(20–25 g) | 3 d | M | N=4 | 92 | ||
| No change MMP-9-immunoreactive glial cells | M | N=4 | |||||
| ↓ Density of glutathione-S-transferase-pi-immunoreactive mature oligodendrocytes | 10–12 w | 28 d | M | N=4–8 | 98 | ||
| Cell/structure (de)generation | WML | 10 w | 14–30 d, not 7 d | M | N=28? | 90 | |
| 10–12 w | 30 d | M | N=24 total? | 91 | |||
| ?(20–25 g) | 28 d or 30 d | M | N=6 | 92 | |||
| ?(22–26 g) | 30 d | M | N=6 | 93 | |||
| 10 w | 14–30 d, not 7 d | M | N=6 | 94 | |||
| 3–4 m | 1–2 m | M | N=37–49? | 95 | |||
| 11 w | 3 w | M | N=5 | 97 | |||
| 10–12 w | 28 d | M | N=7 | 98 | |||
| ?(25–30 g) | 1 m | M | N=8–15 | 118 | |||
| No gray matter infarctions, hemorrhages, or atrophy | 10–12 w | 30 d | M | N=24 total? | 91 | ||
| No apoptosis in the hippocampus | 10–12 w | 30 d | M | N=24 total? | |||
| Ischemic neuronal perikaryal damage | 3–4 m | 1–2 m | M | N=23 out of 49 | 95 | ||
| ?(25–30 g) | 1 m | M | N=2 out of 15 | 118 | |||
| Axonal damage (APP) | 3–4 m | 1–2 m | M | N=? out of 49 | 95 | ||
| ?(25–30 g) | 1 m | M | N=6 out of 13 | 118 | |||
| Gray matter changes and hippocampal atrophy | 16w | 8 m | M | N=4–7 | 89 | ||
| ↓ Mature oligodendrocytes (GST-pi) | ?(22–26 g) | 30 d | M | N=4? | 93 | ||
| No change apoptotic cells | ∼3–4 m | 3 d, 1 m | M | N=8–10 | 150 | ||
| Disrupted axon–glial connections | ∼3–4 m | 3 d, 1 m | M | N=4–10 | |||
| Metabolism | ↓ First 5-min uptake 18F-FDG in the cerebral cortex and striatum, recovery at later time points | 16 w | 2 h | M | N=1–3 | 89 | |
| ↓ First 5-min and late uptake 18F-FDG in hippocampus | 16 w | 6 m, not 2 h–2 m | M | N=1–3 | |||
| AD pathology | No Aβ deposits or axonal APP | 16 w | 8 m | M | N=? | 89 | |
| Cognition | Y-maze: ↓ working memory | 11 w | 2 w, 3 w | M | N=12–15 | 97 | |
| 10–12 w | 1 m | M | N=17–26 | 98 | |||
| MWM: no differences in cued test, spatial reference learning and memory, or serial spatial learning and memory | 3–4 m | 1–2 m/1 m/2 m | M | N=9–14/9–11/11–14 | 95 | ||
| 8-Arm: ↓ working memory | 3–4 m | 2 m | M | N=17–24 | |||
| 8-Arm: ↓ working memory, no difference in reference memory | 14–16 w | 30 d | M | N=10–12/11–13 | 91 | ||
| 8-Arm: ↓ working memory | 16w | 5 m | M | N=14–15 | 89 | ||
| Barnes: ↓ reference memory | 16 w | 6 m | M | N=14–15 | |||
| Contextual and cued fear conditioning: no differences | 10–12 w | 30 d | M | N=11–13 | 91 | ||
| Locomotion | OF+light/dark transition test: no difference in locomotion | 14–16 w | 30 d | M | N=11–13 | 91 | |
| Wire hang+rotarod: no differences | 14–16 w | M | N=11–13 | ||||
| OF: ↑ hyperactivity | 16 w | 2 m | M | N=15–16 | 89 | ||
| Gait+beam test: ↓ motor function | 16 w | 3 m | M | N=11–13/15–16 | |||
| Rotarod: no differences | 16 w | 3 m | M | N=? | |||
| Wire hang test: no differences | 16 w | 4 m | M | N=? | |||
| No difference in spontaneous activity | 10–12 w | 1 m | M | N=17–26 | 98 | ||
| Anxiety | Light/dark transition test: no differences | 14–16 w | 30 d | M | N=11–13 | 91 | |
| Light/dark transition test+elevated plus maze: ↓ anxiety | 16 w | 2 m | M | N=15–16 | 89 | ||
| Behavioral despair | Porsolt forced swim test: no difference | 14–16 w | 30 d | M | N=11–13 | 91 | |
| 16 w | 3 m | M | N=? | 89 | |||
| Neurologic screening | Ear and whisker twitch, righting reflex, and acoustic startle: no differences | 14–16 w | 30 d | M | N=11–13 | 91 | |
| Prepulse inhibition: no difference sensory–motor gating | 14–16 w | 30 d | M | N=11–13 | |||
| Hot-plate test: no differences nociception | 14–16 w | 30 d | M | N=11–13 | |||
| Ear and whisker twitch, righting reflex, and acoustic startle: no differences | 16 w | 2 m | M | N=? | 89 | ||
| Prepulse inhibition: no difference in sensory–motor gating | 16 w | 2 m | M | N=? | |||
| Hot-plate test: no differences nociception | 16 w | 2 m | M | N=? | |||
| Social interaction | Social interaction test: no differences | 16 w | 3 m | M | N=? | ||
Aβ, amyloid β; AD, Alzheimer's disease; APP, amyloid precursor protein; BBB, blood–brain barrier; BCAS, bilateral common carotid artery stenosis; 18F-FDG, fluorodeoxyglucose; 8-arm, Eight-arm radial maze; BBB, blood–brain barrier; CBF, cerebral blood flow; CC, corpus callosum; DA, dopamine; GFAP, glial fibrillary acidic protein; GST, glutathione S-transferase; h, human; ICH, intracerebral hemorrhage; IL, interleukin; m, months; M, male; MHC, major histocompatibility complex; MBP, myelin basic protein; MMP, matrix metalloproteinase; MWM, Morris water maze; NADPH, nicotinamide adenine dinucleotide phosphate; p-eNOS, phosphorylated-endothelial nitric oxide synthase; OF, open field test; ORT, object recognition task; PA, passive avoidance; ROS, reactive oxygen species; SOD, superoxide dismutases; TAC, transverse aortic constriction; TNFα, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; w, weeks; WML, white matter lesions; WT, wild type; ↑, increase; ↓, decrease.
Differences compared with sham WT mice or to baseline measure; (): weeks after surgery; N=amount of animals per group; ?=unknown.
Bilateral Common Carotid Artery Stenosis
Bilateral common carotid artery stenosis (BCAS) is a model for subcortical ischemic vascular dementia89 and is copied from the chronic cerebral hypoperfusion rat model.90 Although in rats both carotid arteries can be fully occluded, the survival rate with full occlusion is very low in mice. Therefore, BCAS mice are created by placing partially occluding external microcoils around both carotid arteries (see Figure 1). The severity of the model can be modified by altering the diameter of the coils.
Cerebral Perfusion and Blood–Brain barrier
With a coil diameter of 0.22 mm the CBF did not change. Smaller coils (0.2, 0.18, or 0.16 mm) did result in acute CBF reductions, with smaller coils having a larger effect.90 Most studies are performed with 0.18 mm coils because of the high mortality rate of constriction with 0.16 mm coils (75%) compared with 0.18 mm coils (15%). The 0.18 mm coils led to a 60% to 70% reduction of the CBF after 2 hours compared with baseline, and increased again gradually to approximately 72% after 1 day, 77% after 7 days, and recovered to 80% to 85% of baseline after 1 to 3 months,89, 90, 91 whereas the blood pressure was not affected.90, 91
Blood–brain barrier permeability (measured by immunoglobulin M and Evans Blue extravasation) followed the acute CBF changes, and increased in the white matter of BCAS mice after 3 days till at least 14 days.92
Gray and White Matter Damage
White matter lesions were present at 14 and 30 days after placement of 0.20, 0.18, and 0.16 mm coils,90, 91, 93, 94 and did not differ in extent after 1 or 2 months of hypoperfusion.95 A reduction in myelinated fiber intensity was seen in the corpus callosum, caudate putamen, internal capsule, and to a lesser extent in the optic tract.90 The WML score significantly correlated with the CBF reduction. Gray matter changes were also reported after 30 days with the use of 0.16 mm coils, including ischemic foci in the cerebral cortex, hippocampus, and basal ganglia.90
In mice with 0.18 mm coils, the gray matter changes take longer to develop; after 30 days or 6 months, no gray matter damage has been observed in most mice, but after 8 months pyknotic neurons are observed in the hippocampus and cerebral cortex.89, 90, 91, 96 In contrast, a different study reported neuronal perikaryal and axonal damage in few mice already after 1 or 2 months.95 Atrophy was only observed in the hippocampus and not in the cerebral cortex or corpus callosum. The CA1 and CA3 sectors were more affected than the dentate gyrus, as shown by the increased number of fragmented or shrunken nuclei.89 Bilateral common carotid artery stenosis mice also showed a reduction in cholinergic fibers, but no difference in choline acetyltransferase-positive cells.
Inflammatory Response
Matrix metalloproteinase-2-immunoreactive glial cells were increased as early as 3 days after BCAS and deletion of the MMP-2 gene reduced severity of WML, BBB disruption, and the amount of inflammation.92 Increasing numbers of activated microglia were observed as soon as 7 days after the operation.90, 93, 95 Increases in WM astrogliosis, microgliosis, and proinflammatory cytokines were mostly not yet observed after 7 days, but was observed after 14 days.90, 94, 97 The exact mechanisms underlying the cerebral damage due to hypoperfusion are not fully understood, but the rennin–angiotensin system and oxidative stress appear to be involved. A study by Dong et al97 showed that cerebral hypoxia, inflammation, WML, and increase in renin, a blood pressure-regulating enzyme, induced by BCAS can be improved by aliskiren (renin inhibitor) and Tempol (superoxide scavenger).97
Metabolism
Also, metabolic abnormalities have been observed in BCAS mice. Two hours after BCAS, the first 5-minute uptake of fluorodeoxyglucose (18F-FDG) was decreased in the striatum and cerebral cortex; FDG uptake slowly recovered to 88% in the cerebral cortex after 2 months. In contrast, in the hippocampus, FDG uptake was initially maintained (after 2 hours and 2 months), but was deteriorated after 6 months.89
Cognitive and Behavioral Changes
Working memory deficits have been observed with the 8-arm radial maze in BCAS mice with 0.18 mm coils after 1, 2, and 5 to 6 months.89, 91, 95 Although reference memory (8-arm radial maze) was not different after 30 days, it was impaired after 5 to 6 months when tested with the Barnes maze. The number of revisiting errors correlated with the CBF reduction from 7 days until at least 28 days after BCAS surgery.98 Spatial reference and serial spatial learning and memory measured with the MWM were not affected by BCAS after 1 and 2 months.95
Other behavioral characteristics, such as sensory–motor reflexes or gating, nociception, motor coordination, locomotor activity, behavioral despair, and contextual or cued fear conditioning did not show significant changes after 30 days.91 These findings indicate that the working memory impairment after 30 days was not due to physical characteristics, motor, or sensory deficits. Because of the observed histologic damage, the functional deficits become more pronounced as the hypoperfusion persists; after 3 months, locomotion and motor function were impaired.89
As said before, the extent of damage strongly depends on the severity of the model. In a study with mice receiving an asymmetric carotid stenosis (0.16-mm coil diameter left and 0.18-mm coil diameter right), it was nicely shown that moderate hypoperfusion results in a spatial reference memory dysfunction in the hidden platform test. However, in more severely affected animals, also the visual acuity and locomotion were affected,99 and in those cases, the outcomes of the MWM cannot be attributed only to cognitive function.
Relation to Alzheimer's disease
In contrast to the TAC model, no Aβ deposits or axonal APPs have been detected in the hippocampus or cerebral cortex in WT mice after 8 months.89
The combination of BCAS with APP-overexpressing models has led to an accelerated pathogenesis. The transgenic mouse model for cerebral amyloid angiopathy that expresses human vasculotropic Swedish/Dutch/Iowa mutant APP (called the Tg-SwDI mice) is one of the widely used models for Alzheimer research. Microinfarcts have been shown in a subset of Tg-SwDI mice with BCAS at 18 to 32 weeks, which were not found at these ages in Tg-SwDI mice without BCAS or WT mice with BCAS.100 The Tg-SwDI mice also showed a more pronounced CBF decrease than WT mice when subjected to BCAS. Furthermore, BCAS led to accelerated deposition of Aβ in Tg-SwDI mice100 and in APPSwInd mice, a model expressing the Swedish and Indiana APP mutations.101 The latter model also exhibited an increase in activated astroglia and apoptotic cells 12 months after surgery.
In conclusion, BCAS mice have decreased CBF, increased inflammation and BBB permeability, brain atrophy, WML, decreased metabolism, and impaired cognition, thus mimicking many aspects of VCI in patients.
Other Cardiovascular Mouse Models
Other relevant models are hypertension models and models for CADASIL. Hypertension is thought to be the most important cause for cerebrovascular disease. There is however not much known about the cerebral effects of chronic hypertension models. The most important findings are reduced CBF, increased BBB permeability, and other related vascular abnormalities (see Supplementary Table 2).
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an inherited neurovascular disorder caused by mutations in the Notch3 receptor.102 It is a small vessel disease of the brain, which causes recurrent ischemic strokes with cognitive impairment and dementia.103, 104 There are several genetic mouse models for CADASIL, most with a mutation in the Notch3 gene. The specific mutation and the expression level of Notch3 may determine the observed changes.105 Supplementary Table 3 summarizes results for the three functionally active mutations R90C, R169C, and R170C. In addition, one mutated Notch1 mouse model has been generated and assessed for cognitive function (see Supplementary Table 3). The different CADASIL mouse models are reviewed elsewhere.104
Conclusions
Vascular Cognitive Impairment: Which is the Best Model and Why?
The optimal mouse model to study VCI should have similar pathophysiology as VCI patients (face validity), comparable etiology (construct validity), and predict which treatments do and do not have a therapeutic value (predictive validity).
Regarding the face validity, the animals should have reduced cerebral perfusion, inflammation, BBB alterations, WMLs, and cognitive deficits.3 The animal models in this review are selected based on construct validity evidence, i.e., atherosclerosis, HF, hypertension, or CADASIL. Because hypoperfusion is associated with these diseases, hypoperfusion models represent an additional interesting candidate model. Predictive validity should be an important condition in future evaluation of the optimal animal model. However, as there are currently no treatments known to be effective in VCI patients, it is not yet possible to test the predictive validity. End points on which predictive validity should be based are cognition, and as early end points, inflammation, BBB alterations, and WMLs. In addition, a good model should ideally only represent one particular CVD at a time, and be reversible by mechanical or pharmacological modulation. Only then we can study the molecular and cellular mechanisms involved and assess whether the cerebral damage and cognitive changes are reversible.
With the current knowledge, the model that, in our opinion, best fulfils these criteria is the BCAS model (see Table 6), as it induces cerebral hypoperfusion, decreased BBB integrity, cerebral inflammation, WML, decreased metabolism, and cognitive deficits. Bilateral common carotid artery stenosis is the only CVD mouse model in which WML have been observed. This surgery-induced model may be (partly) reversible, although no studies have been published as yet where this is actually shown. A second advantage in contrast to genetic models is the exclusion of possible developmental changes due to the genetic manipulation. A third advantage is that in a later stage this surgery-induced model can be combined with genetic models to study mixed pathologies, as has already been done with AD models.
Table 6. Structural and functional changes in the discussed mouse models.
| ApoE−/− | hApoB | LDLr−/− | LDLr−/− × hApoB | TAC | MI | BCAS | |
|---|---|---|---|---|---|---|---|
| Cerebral blood flow | ↓ | ? | ? | ↓ | ↓ | ↓ | ↓ |
| BBB permeability | ↑ | ? | x (≤9 w) | ? | ↑ | ? | ↑ |
| Microvascular alterations | ? | ? | ↑ | ↑ | ? | ? | ↑ |
| Inflammation | ↑ | ? | ↑ | ↑ | ↑ | ↑ | ↑ |
| Oxidative stress | ? | ? | ↑ | ? | ↑ | ? | ↑ |
| White matter lesions | ? | ? | x (≤14 m) | ? | ? | ? | ↑ |
| Cellular/structural loss | ↑/x | ↑ | ↑ | ↑ | x (≤8 w) | x (≤6 w) | ↑ |
| Metabolism | ↓ | ? | ↓ | ? | ↓ | ? | ↓ |
| Aβ deposits | ? | ↑ | x (≤6 m) | ↑ | ↑ | ? | x (≤8 m) |
| Cognition | ↓ | ? | ↓ | ↓ | ↓ | x (≤6 w) | ↓ |
Aβ, amyloid β; Apo, apolipoprotein; BBB, blood–brain barrier; BCAS, bilateral common carotid artery stenosis; hApoB, human ApoB; LDLr, low-density lipoprotein receptor; months; m, months; MI, myocardial infraction; TAC, transverse aortic constriction; w, weeks; ↓, decrease; ↑, increase; ?=unknown, not published data.
One disadvantage of the BCAS model is that it is very sensitive to the degree of ligation. As discussed above, variations of 0.02 mm in coil diameter make the difference between gray matter loss at 1 month after surgery or only after 8 months. Furthermore, the visual performance may also be affected and needs to be tested to exclude a confounding effect of damage in the visual pathway as seen in BCAS rats.
Alternatives to the BCAS model are two other operation-induced models, namely the MI and TAC models. Because there is limited cerebral data for the MI model, it is not known whether MI mice show all the relevant pathologic and cognitive effects. The cerebral effects of the TAC model are only studied by one experimental group and reproducibility of the cerebral effects first has to be established. A potential drawback is that TAC placement does not always lead to left ventricular hypertrophy, and therefore cerebral effects may be heterogeneous. This drawback can be prevented by selecting only responsive mice based on the pressure gradient across the transverse aorta.106 White matter lesions and long-term effects still have to be investigated in this model.
Atherosclerosis models may also be used to study CVD effects on cerebral perfusion, structure, and functioning. In models with a substantial atherosclerotic load, such as in ApoE−/− and LDLr−/− × hApoB mice, (micro)vascular dysfunction has been reported (see Table 6). In milder atherosclerosis models, data were not conclusive and different time points need to be tested. Apolipoprotein E−/− is a commonly used model to study atherosclerosis and AD. However, it is difficult to determine which effects are due to atherosclerosis and which are due to direct effects of ApoE on the brain through, e.g., Aβ clearance and deposition.107 Therefore, an atherosclerotic mouse model with an intact ApoE gene is preferred.
In addition to the clean models summarized above, combinations of different models are needed in a later stage to study additive or combined effects and to investigate whether the different CVD have common mechanisms in creating cerebral changes and cognitive effects. This knowledge is important for determining the molecular targets for potential pharmacological treatments. These combined models will also represent a great amount of patients who have multiple risk factors and diseases.
The TAC model represents such a mixed model for hypertension and HF. Atherosclerotic models can be mixed with cerebral hypoperfusion models or with HF models representing atherosclerosis in the end stage of the disease.
Also in AD research, there is accumulating evidence that vascular dysfunction and hypoperfusion have an important role in the pathogenesis of the disease.12, 108, 109 Mixtures of AD models with CVD models are already studied in, e.g., BCAS and LDLr−/− mice, showing aggravated pathology, CBF reduction, and cognitive dysfunction.71, 100, 101
Mechanistical Insides and Future Directions
As our review clearly shows that the available data on mouse models to study VCI are diverse, we need to define a standard set of measurements in each candidate model, which is to be tested at different time points. This set needs to include data on cerebral perfusion, microvascular inflammation, WMLs, BBB integrity, and behavior (especially cognition).3 Different time points are needed to unravel the sequence of events (see Figure 2).
Figure 2.
Proposed flow chart of disease progression primarily based on experimental data of the BCAS and TAC model. Because not a lot of successive studies have been performed, no clear distinction between cause and result of the different factors can be made. Aβ, amyloid β; ApoE, apolipoprotein; BBB, blood–brain barrier; BCAS, bilateral common carotid artery stenosis; TAC, transverse aortic constriction; WML, white matter lesion.
Besides cognitive tests, behavioral tests such as motor function and anxiety should be performed in all animal models to ensure that the results of cognitive tests are not affected by locomotion or anxiety. Moreover, multiple cognitive tests studying different cognitive domains should be included to study the specific cognitive phenotype.
Besides causal and pathologic differences, VCI and AD patients may have different clinical phenotypes. Vascular cognitive impairment patients tend to have more severe impairment in executive functions compared with AD patients.110 However, results are not consistent111 and it is not yet possible to make a clear distinction based on clinical phenotype. In animal models, generally only learning and memory is tested, whereas other cognitive deficits are frequently neglected. Because memory impairment is not required for the diagnosis of VCI and other cognitive deficits may be more important in VCI, it is important to extend the behavioral and cognitive test battery in these animal models.
Cerebral perfusion should be an important feature in future studies, but has yet not been measured in many models. In vivo techniques to study cerebral perfusion are MRI,112 SPECT,113 laser Doppler flowmetry,90, 99 laser speckle flowmetry,114 computed totmography,115 diffuse correlation spectroscopy116 and two-photon microscopy.117 There are however great differences between methods in the sensitivity, area size, location, and spatial resolution.116
Blood–brain barrier integrity can be examined in vivo by contrast-enhanced MRI. Histologically, the permeability is assessed by the presence of larger molecules, such as albumin, immunoglobulin G, or Evans Blue, that only penetrate the brain in case of increased permeability.41, 79 More subtle damage can be detected by analyzing the microvascular structure.105
Measuring white matter damage is problematic because of the small amount of white matter in rodents. However, in the BCAS model it has been shown that it is possible to reproduce the finding of WML in mice by multiple groups.90, 94, 118
Inflammation is an important pathologic feature in VCI and is involved in several other neurodegenerative diseases such as AD.3, 119, 120 All CVD mouse models that have been discussed in this review show an increase in inflammation. In both the ApoE−/− and the TAC model, an inflammatory pathway has shown to be a primary factor in the cerebral pathology. An important player across all the models discussed is MMP-9. Matrix metalloproteinase-9 may be activated directly through the proinflammatory CypA–nuclear factor-κB–MMP-9 pathway.36 Alternatively, RAGE and the TNF-α–sphingosine 1–sphingosine-1-phosphate pathway have also been show to be important for HF in mouse models,86, 88 and both are known to influence MMP-9 activity.121, 122 Increased MMP-9 activity has also been found in LDLr−/− × hApoB and the HF model CA/ cardiac arrest/cardiopulmonary resuscitation.76, 123 Both RAGE and MMP-9 have been implicated in human studies of vascular dementia and AD.124, 125, 126 Matrix metalloproteinases are also known for their influence on neuronal loss and synaptic plasticity.127, 128, 129 Altogether, inflammation appears to be one of the important processes present at the beginning of the pathology leading to cognitive impairment as a consequence of CVD.
Cerebral hypoperfusion may indeed be an important trigger to inflammation and cognitive impairment.12, 89, 90 Cerebral hypoperfusion is associated with VCI, improvement of brain perfusion in humans leads to an improvement of cognitive function, and, intriguingly, the induction of cerebral hypoperfusion in mice leads to a VCI phenotype. However, the mechanisms underlying these observations remain largely elusive as most factors are interrelated and more time points need to be studied in the different mouse models to dissect clearly the mechanisms involved and the order of events in the disease progression (Figure 2). Although there is accumulating evidence that vascular dysfunction and hypoperfusion also have an important role in AD, and mixtures of AD models with CVD models like BCAS and LDLr−/− mice significantly increase the progression of the disease progression, this research will not only be important for the pure VCI and vascular dementia syndromes but also will have a much larger impact on our understanding of neurodegenerative diseases.
The authors declare no conflict of interest.
Footnotes
Supplementary Information accompanies the paper on the Journal of Cerebral Blood Flow & Metabolism website (http://www.nature.com/jcbfm)
Supplementary Material
References
- Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63–75, e2. doi: 10.1016/j.jalz.2012.11.007. [DOI] [PubMed] [Google Scholar]
- Ott A, Breteler MM, van Harskamp F, Claus JJ, van der Cammen TJ, Grobbee DE, et al. Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study. BMJ. 1995;310:970–973. doi: 10.1136/bmj.310.6985.970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2011;42:2672–2713. doi: 10.1161/STR.0b013e3182299496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prince M. Epidemiology of dementia. Psychiatry. 2007;6:488–490. [Google Scholar]
- Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail. 2007;9:440–449. doi: 10.1016/j.ejheart.2006.11.001. [DOI] [PubMed] [Google Scholar]
- Skoog I. Hypertension and cognition. Int Psychogeriatr. 2003;15 (Suppl 1:139–146. doi: 10.1017/S1041610203009104. [DOI] [PubMed] [Google Scholar]
- Bos D, Vernooij MW, Elias-Smale SE, Verhaaren BF, Vrooman HA, Hofman A, et al. Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging. Alzheimers Dement. 2012;8:S104–S111. doi: 10.1016/j.jalz.2012.01.008. [DOI] [PubMed] [Google Scholar]
- Wendell CR, Waldstein SR, Ferrucci L, O'Brien RJ, Strait JB, Zonderman AB. Carotid atherosclerosis and prospective risk of dementia. Stroke. 2012;43:3319–3324. doi: 10.1161/STROKEAHA.112.672527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Qiu C, Winblad B, Marengoni A, Klarin I, Fastbom J, Fratiglioni L. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med. 2006;166:1003–1008. doi: 10.1001/archinte.166.9.1003. [DOI] [PubMed] [Google Scholar]
- van Oijen M, De Jong FJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. Atherosclerosis and risk for dementia. Ann Neurol. 2007;61:403–410. doi: 10.1002/ana.21073. [DOI] [PubMed] [Google Scholar]
- Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007;64:1734–1740. doi: 10.1001/archneur.64.12.1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de la Torre JC. Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia. Cardiovasc Psychiatry Neurol. 2012;2012:367516. doi: 10.1155/2012/367516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marshall RS. Effects of altered cerebral hemodynamics on cognitive function. J Alzheimers Dis. 2012;32:633–642. doi: 10.3233/JAD-2012-120949. [DOI] [PubMed] [Google Scholar]
- Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol. 2005;57:789–794. doi: 10.1002/ana.20493. [DOI] [PubMed] [Google Scholar]
- Kitagawa K. Cerebral blood flow measurement by PET in hypertensive subjects as a marker of cognitive decline. J Alzheimers Dis. 2010;20:855–859. doi: 10.3233/JAD-2010-091324. [DOI] [PubMed] [Google Scholar]
- Kitagawa K, Oku N, Kimura Y, Yagita Y, Sakaguchi M, Hatazawa J, et al. Relationship between cerebral blood flow and later cognitive decline in hypertensive patients with cerebral small vessel disease. Hypertens Res. 2009;32:816–820. doi: 10.1038/hr.2009.100. [DOI] [PubMed] [Google Scholar]
- van Beek AH, Claassen JA, Rikkert MG, Jansen RW. Cerebral autoregulation: an overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab. 2008;28:1071–1085. doi: 10.1038/jcbfm.2008.13. [DOI] [PubMed] [Google Scholar]
- Roman DD, Kubo SH, Ormaza S, Francis GS, Bank AJ, Shumway SJ. Memory improvement following cardiac transplantation. J Clin Exp Neuropsychol. 1997;19:692–697. doi: 10.1080/01688639708403754. [DOI] [PubMed] [Google Scholar]
- Zuccala G, Onder G, Marzetti E, Monaco MR, Cesari M, Cocchi A, et al. Use of angiotensin-converting enzyme inhibitors and variations in cognitive performance among patients with heart failure. Eur Heart J. 2005;26:226–233. doi: 10.1093/eurheartj/ehi058. [DOI] [PubMed] [Google Scholar]
- Hoth KF, Poppas A, Ellison KE, Paul RH, Sokobin A, Cho Y, et al. Link between change in cognition and left ventricular function following cardiac resynchronization therapy. J Cardiopulm Rehabil Prev. 2010;30:401–408. doi: 10.1097/HCR.0b013e3181e1739a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cheng Y, Wang YJ, Yan JC, Zhou R, Zhou HD. Effects of carotid artery stenting on cognitive function in patients with mild cognitive impairment and carotid stenosis. Exp Ther Med. 2013;5:1019–1024. doi: 10.3892/etm.2013.954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vogels RL, van der Flier WM, van Harten B, Gouw AA, Scheltens P, Schroeder-Tanka JM, et al. Brain magnetic resonance imaging abnormalities in patients with heart failure. Eur J Heart Fail. 2007;9:1003–1009. doi: 10.1016/j.ejheart.2007.07.006. [DOI] [PubMed] [Google Scholar]
- Romero JR, Beiser A, Seshadri S, Benjamin EJ, Polak JF, Vasan RS, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke. 2009;40:1590–1596. doi: 10.1161/STROKEAHA.108.535245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke. Trends Neurosci. 2007;30:433–439. doi: 10.1016/j.tins.2007.06.009. [DOI] [PubMed] [Google Scholar]
- Samaranayake S. Study Quality in Experimental Stroke. University of Edinburgh: Edinburgh; 2006. [Google Scholar]
- Macleod MR, O'Collins T, Horky LL, Howells DW, Donnan GA. Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cerebr Blood F Met. 2005;25:713–721. doi: 10.1038/sj.jcbfm.9600064. [DOI] [PubMed] [Google Scholar]
- Macleod MR, O'Collins T, Horky LL, Howells DW, Donnan GA. Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res. 2005;38:35–41. doi: 10.1111/j.1600-079X.2004.00172.x. [DOI] [PubMed] [Google Scholar]
- Macleod MR, O'Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. 2004;35:1203–1208. doi: 10.1161/01.STR.0000125719.25853.20. [DOI] [PubMed] [Google Scholar]
- Lukasik VM, Gillies RJ. Animal anaesthesia for in vivo magnetic resonance. NMR Biomed. 2003;16:459–467. doi: 10.1002/nbm.836. [DOI] [PubMed] [Google Scholar]
- Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204–212. doi: 10.1038/ni.2001. [DOI] [PubMed] [Google Scholar]
- Daugherty A. Mouse models of atherosclerosis. Am J Med Sci. 2002;323:3–10. doi: 10.1097/00000441-200201000-00002. [DOI] [PubMed] [Google Scholar]
- Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
- Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994;14:133–140. doi: 10.1161/01.atv.14.1.133. [DOI] [PubMed] [Google Scholar]
- Methia N, Andre P, Hafezi-Moghadam A, Economopoulos M, Thomas KL, Wagner DD. ApoE deficiency compromises the blood brain barrier especially after injury. Mol Med. 2001;7:810–815. [PMC free article] [PubMed] [Google Scholar]
- Sheng H, Laskowitz DT, Mackensen GB, Kudo M, Pearlstein RD, Warner DS. Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke. 1999;30:1118–1124. doi: 10.1161/01.str.30.5.1118. [DOI] [PubMed] [Google Scholar]
- Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485:512–516. doi: 10.1038/nature11087. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, et al. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun. 2011;25:1113–1122. doi: 10.1016/j.bbi.2011.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood–brain barrier model. J Biol Chem. 2011;286:17536–17542. doi: 10.1074/jbc.M111.225532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hafezi-Moghadam A, Thomas KL, Wagner DD. ApoE deficiency leads to a progressive age-dependent blood–brain barrier leakage. Am J Physiol Cell Physiol. 2007;292:C1256–C1262. doi: 10.1152/ajpcell.00563.2005. [DOI] [PubMed] [Google Scholar]
- Mulder M, Blokland A, van den Berg DJ, Schulten H, Bakker AH, Terwel D, et al. Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood–brain barrier during aging. Lab Invest. 2001;81:953–960. doi: 10.1038/labinvest.3780307. [DOI] [PubMed] [Google Scholar]
- Fullerton SM, Shirman GA, Strittmatter WJ, Matthew WD.Impairment of the blood–nerve and blood–brain barriers in apolipoprotein e knockout mice Exp Neurol 200116913–22.11312553 [Google Scholar]
- Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell. 2009;5:634–645. doi: 10.1016/j.stem.2009.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang CP, Gilley JA, Zhang G, Kernie SG. ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development. 2011;138:4351–4362. doi: 10.1242/dev.065540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krugers HJ, Mulder M, Korf J, Havekes L, de Kloet ER, Joels M. Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E deficient mice. NeuroReport. 1997;8:2505–2510. doi: 10.1097/00001756-199707280-00018. [DOI] [PubMed] [Google Scholar]
- Valastro B, Ghribi O, Poirier J, Krzywkowski P, Massicotte G. AMPA receptor regulation and LTP in the hippocampus of young and aged apolipoprotein E-deficient mice. Neurobiol Aging. 2001;22:9–15. doi: 10.1016/s0197-4580(00)00177-9. [DOI] [PubMed] [Google Scholar]
- Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD. Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol. 1995;136:107–122. doi: 10.1006/exnr.1995.1088. [DOI] [PubMed] [Google Scholar]
- Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, et al. Expression of human apolipoprotein E3 or E4 in the brains of Apoe−/− mice: isoform-specific effects on neurodegeneration. J Neurosci. 1999;19:4867–4880. doi: 10.1523/JNEUROSCI.19-12-04867.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grootendorst J, de Kloet ER, Dalm S, Oitzl MS. Reversal of cognitive deficit of apolipoprotein E knockout mice after repeated exposure to a common environmental experience. Neuroscience. 2001;108:237–247. doi: 10.1016/s0306-4522(01)00412-2. [DOI] [PubMed] [Google Scholar]
- Grootendorst J, Oitzl MS, Dalm S, Enthoven L, Schachner M, de Kloet ER, et al. Stress alleviates reduced expression of cell adhesion molecules (NCAM, L1), and deficits in learning and corticosterone regulation of apolipoprotein E knockout mice. Eur J Neurosci. 2001;14:1505–1514. doi: 10.1046/j.0953-816x.2001.01766.x. [DOI] [PubMed] [Google Scholar]
- Grootendorst J, Enthoven L, Dalm S, de Kloet ER, Oitzl MS. Increased corticosterone secretion and early-onset of cognitive decline in female apolipoprotein E-knockout mice. Behav Brain Res. 2004;148:167–177. doi: 10.1016/s0166-4328(03)00188-8. [DOI] [PubMed] [Google Scholar]
- Veinbergs I, Mallory M, Mante M, Rockenstein E, Gilbert JR, Masliah E. Differential neurotrophic effects of apolipoprotein E in aged transgenic mice. Neurosci Lett. 1999;265:218–222. doi: 10.1016/s0304-3940(99)00243-8. [DOI] [PubMed] [Google Scholar]
- Veinbergs I, Mante M, Jung MW, Van Uden E, Masliah E. Synaptotagmin and synaptic transmission alterations in apolipoprotein E-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:519–531. doi: 10.1016/s0278-5846(99)00013-5. [DOI] [PubMed] [Google Scholar]
- Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, et al. Clearance of Alzheimer's amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J Clin Invest. 2000;106:1489–1499. doi: 10.1172/JCI10498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Genis L, Chen Y, Shohami E, Michaelson DM. Tau hyperphosphorylation in apolipoprotein E-deficient and control mice after closed head injury. J Neurosci Res. 2000;60:559–564. doi: 10.1002/(SICI)1097-4547(20000515)60:4<559::AID-JNR15>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
- Katsouri L, Georgopoulos S. Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model. PLoS One. 2011;6:e21880. doi: 10.1371/journal.pone.0021880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997;17:263–264. doi: 10.1038/ng1197-263. [DOI] [PubMed] [Google Scholar]
- Purcell-Huynh DA, Farese RV, Jr., Johnson DF, Flynn LM, Pierotti V, Newland DL, et al. Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. J Clin Invest. 1995;95:2246–2257. doi: 10.1172/JCI117915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Csont T, Bereczki E, Bencsik P, Fodor G, Gorbe A, Zvara A, et al. Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice. Cardiovasc Res. 2007;76:100–109. doi: 10.1016/j.cardiores.2007.06.006. [DOI] [PubMed] [Google Scholar]
- Bereczki E, Bernat G, Csont T, Ferdinandy P, Scheich H, Santha M. Overexpression of human apolipoprotein B-100 induces severe neurodegeneration in transgenic mice. J Proteome Res. 2008;7:2246–2252. doi: 10.1021/pr7006329. [DOI] [PubMed] [Google Scholar]
- Hobbs HH, Brown MS, Russell DW, Davignon J, Goldstein JL. Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med. 1987;317:734–737. doi: 10.1056/NEJM198709173171204. [DOI] [PubMed] [Google Scholar]
- Oliveira JD, Hort MA, Moreira EL, Glaser V, Ribeiro-do-Valle RM, Prediger RD, et al. Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress. Neuroscience. 2011;197:99–106. doi: 10.1016/j.neuroscience.2011.09.009. [DOI] [PubMed] [Google Scholar]
- Elder GA, Cho JY, English DF, Franciosi S, Schmeidler J, Sosa MA, et al. Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor. J Neurochem. 2007;102:1220–1231. doi: 10.1111/j.1471-4159.2007.04614.x. [DOI] [PubMed] [Google Scholar]
- Taha AY, Chen CT, Liu Z, Kim JH, Mount HT, Bazinet RP. Brainstem concentrations of cholesterol are not influenced by genetic ablaqtion of the low-density lipoprotein receptor. Neurochem Res. 2009;34:311–315. doi: 10.1007/s11064-008-9777-7. [DOI] [PubMed] [Google Scholar]
- Osono Y, Woollett LA, Herz J, Dietschy JM. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J Clin Invest. 1995;95:1124–1132. doi: 10.1172/JCI117760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Franciosi S, Gama Sosa MA, English DF, Oler E, Oung T, Janssen WG, et al. Novel cerebrovascular pathology in mice fed a high cholesterol diet. Mol Neurodegener. 2009;4:42. doi: 10.1186/1750-1326-4-42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, et al. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem. 2008;106:475–485. doi: 10.1111/j.1471-4159.2008.05415.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mulder M, Jansen PJ, Janssen BJ, van de Berg WD, van der Boom H, Havekes LM, et al. Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus. Neurobiol Dis. 2004;16:212–219. doi: 10.1016/j.nbd.2004.01.015. [DOI] [PubMed] [Google Scholar]
- Mulder M, Koopmans G, Wassink G, Al Mansouri G, Simard ML, Havekes LM, et al. LDL receptor deficiency results in decreased cell proliferation and presynaptic bouton density in the murine hippocampus. Neurosci Res. 2007;59:251–256. doi: 10.1016/j.neures.2007.07.004. [DOI] [PubMed] [Google Scholar]
- Elder GA, Ragnauth A, Dorr N, Franciosi S, Schmeidler J, Haroutunian V, et al. Increased locomotor activity in mice lacking the low-density lipoprotein receptor. Behav Brain Res. 2008;191:256–265. doi: 10.1016/j.bbr.2008.03.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fryer JD, Demattos RB, McCormick LM, O'Dell MA, Spinner ML, Bales KR, et al. The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem. 2005;280:25754–25759. doi: 10.1074/jbc.M502143200. [DOI] [PubMed] [Google Scholar]
- Cao D, Fukuchi K, Wan H, Kim H, Li L. Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol Aging. 2006;27:1632–1643. doi: 10.1016/j.neurobiolaging.2005.09.011. [DOI] [PubMed] [Google Scholar]
- Sanan DA, Newland DL, Tao R, Marcovina S, Wang J, Mooser V, et al. Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a) Proc Natl Acad Sci USA. 1998;95:4544–4549. doi: 10.1073/pnas.95.8.4544. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Drouin A, Bolduc V, Thorin-Trescases N, Belanger E, Fernandes P, Baraghis E, et al. Catechin treatment improves cerebrovascular flow-mediated dilation and learning abilities in atherosclerotic mice. Am J Physiol Heart Circ Physiol. 2011;300:H1032–H1043. doi: 10.1152/ajpheart.00410.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Powell-Braxton L, Veniant M, Latvala RD, Hirano KI, Won WB, Ross J, et al. A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet. Nat Med. 1998;4:934–938. doi: 10.1038/nm0898-934. [DOI] [PubMed] [Google Scholar]
- Ramirez C, Sierra S, Tercero I, Vazquez JA, Pineda A, Manrique T, et al. ApoB100/LDLR−/− hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage. PLoS One. 2011;6:e22712. doi: 10.1371/journal.pone.0022712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bolduc V, Drouin A, Gillis MA, Duquette N, Thorin-Trescases N, Frayne-Robillard I, et al. Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice. Am J Physiol Heart Circ Physiol. 2011;301:H2081–H2092. doi: 10.1152/ajpheart.00706.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang J, Ji Y, Mehta P, Bates KA, Sun Y, Wisniewski T. Blocking the apolipoprotein E/amyloid-beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. J Alzheimers Dis. 2011;24:269–285. doi: 10.3233/JAD-2011-101401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, et al. Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease. Proc Natl Acad Sci USA. 2006;103:18787–18792. doi: 10.1073/pnas.0604011103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Poulet R, Gentile MT, Vecchione C, Distaso M, Aretini A, Fratta L, et al. Acute hypertension induces oxidative stress in brain tissues. J Cereb Blood Flow Metab. 2006;26:253–262. doi: 10.1038/sj.jcbfm.9600188. [DOI] [PubMed] [Google Scholar]
- Gentile MT, Poulet R, Di Pardo A, Cifelli G, Maffei A, Vecchione C, et al. Beta-amyloid deposition in brain is enhanced in mouse models of arterial hypertension. Neurobiol Aging. 2009;30:222–228. doi: 10.1016/j.neurobiolaging.2007.06.005. [DOI] [PubMed] [Google Scholar]
- Chintalgattu V, Ai D, Langley R, Zhang J, Bankson J, Shih T, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest. 2010;120:472–484. doi: 10.1172/JCI39434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamura A, Rokosh D, Paccanaro M, Yee R, Simpson P, Grossman W, et al. LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice. Am J Physiol Heart Circ Physiol. 2001;281:H1104–H1112. doi: 10.1152/ajpheart.2001.281.3.H1104. [DOI] [PubMed] [Google Scholar]
- Li YH, Hsieh CY, Wang DL, Chung HC, Liu SL, Chao TH, et al. Remodeling of carotid arteries is associated with increased expression of thrombomodulin in a mouse transverse aortic constriction model. Thromb Haemost. 2007;97:658–664. [PubMed] [Google Scholar]
- Li YH, Reddy AK, Taffet GE, Michael LH, Entman ML, Hartley CJ. Doppler evaluation of peripheral vascular adaptations to transverse aortic banding in mice. Ultrasound Med Biol. 2003;29:1281–1289. doi: 10.1016/s0301-5629(03)00986-4. [DOI] [PubMed] [Google Scholar]
- Carnevale D, Mascio G, Ajmone-Cat MA, D'Andrea I, Cifelli G, Madonna M, et al. Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging. 2012;33:205, e19–e29. doi: 10.1016/j.neurobiolaging.2010.08.013. [DOI] [PubMed] [Google Scholar]
- Carnevale D, Mascio G, D'Andrea I, Fardella V, Bell RD, Branchi I, et al. Hypertension induces brain beta-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension. 2012;60:188–197. doi: 10.1161/HYPERTENSIONAHA.112.195511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012;122:1377–13792. doi: 10.1172/JCI58642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang J, Noyan-Ashraf MH, Meissner A, Voigtlaender-Bolz J, Kroetsch JT, Foltz W, et al. Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-alpha-dependent activation of sphingosine-1-phosphate signaling. Circulation. 2012;126:196–206. doi: 10.1161/CIRCULATIONAHA.111.039644. [DOI] [PubMed] [Google Scholar]
- Nishio K, Ihara M, Yamasaki N, Kalaria RN, Maki T, Fujita Y, et al. A mouse model characterizing features of vascular dementia with hippocampal atrophy. Stroke. 2010;41:1278–1284. doi: 10.1161/STROKEAHA.110.581686. [DOI] [PubMed] [Google Scholar]
- Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke. 2004;35:2598–2603. doi: 10.1161/01.STR.0000143725.19053.60. [DOI] [PubMed] [Google Scholar]
- Shibata M, Yamasaki N, Miyakawa T, Kalaria RN, Fujita Y, Ohtani R, et al. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke. 2007;38:2826–2832. doi: 10.1161/STROKEAHA.107.490151. [DOI] [PubMed] [Google Scholar]
- Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R, et al. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006;37:2816–2823. doi: 10.1161/01.STR.0000244808.17972.55. [DOI] [PubMed] [Google Scholar]
- Fujita Y, Ihara M, Ushiki T, Hirai H, Kizaka-Kondoh S, Hiraoka M, et al. Early protective effect of bone marrow mononuclear cells against ischemic white matter damage through augmentation of cerebral blood flow. Stroke. 2010;41:2938–2943. doi: 10.1161/STROKEAHA.110.596379. [DOI] [PubMed] [Google Scholar]
- Duan W, Gui L, Zhou Z, Liu Y, Tian H, Chen JF, et al. Adenosine A2A receptor deficiency exacerbates white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion in mice. J Neurol Sci. 2009;285:39–45. doi: 10.1016/j.jns.2009.05.010. [DOI] [PubMed] [Google Scholar]
- Coltman R, Spain A, Tsenkina Y, Fowler JH, Smith J, Scullion G, et al. Selective white matter pathology induces a specific impairment in spatial working memory. Neurobiol Aging. 2011;32:e7–e12. doi: 10.1016/j.neurobiolaging.2010.09.005. [DOI] [PubMed] [Google Scholar]
- Yamada M, Ihara M, Okamoto Y, Maki T, Washida K, Kitamura A, et al. The influence of chronic cerebral hypoperfusion on cognitive function and amyloid beta metabolism in APP overexpressing mice. PLoS One. 2011;6:e16567. doi: 10.1371/journal.pone.0016567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dong YF, Kataoka K, Toyama K, Sueta D, Koibuchi N, Yamamoto E, et al. Attenuation of brain damage and cognitive impairment by direct renin inhibition in mice with chronic cerebral hypoperfusion. Hypertension. 2011;58:635–642. doi: 10.1161/HYPERTENSIONAHA.111.173534. [DOI] [PubMed] [Google Scholar]
- Maki T, Ihara M, Fujita Y, Nambu T, Miyashita K, Yamada M, et al. Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice. Stroke. 2011;42:1122–1128. doi: 10.1161/STROKEAHA.110.603399. [DOI] [PubMed] [Google Scholar]
- Miki K, Ishibashi S, Sun L, Xu H, Ohashi W, Kuroiwa T, et al. Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice. J Neurosci Res. 2009;87:1270–1281. doi: 10.1002/jnr.21925. [DOI] [PubMed] [Google Scholar]
- Okamoto Y, Yamamoto T, Kalaria RN, Senzaki H, Maki T, Hase Y, et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 2012;123:381–394. doi: 10.1007/s00401-011-0925-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, et al. Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. Brain Res. 2009;1294:202–210. doi: 10.1016/j.brainres.2009.07.078. [DOI] [PubMed] [Google Scholar]
- Wallays G, Nuyens D, Silasi-Mansat R, Souffreau J, Callaerts-Vegh Z, Van Nuffelen A, et al. Notch3 Arg170Cys knock-in mice display pathologic and clinical features of the neurovascular disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arterioscler Thromb Vasc Biol. 2011;31:2881–2888. doi: 10.1161/ATVBAHA.111.237859. [DOI] [PubMed] [Google Scholar]
- Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy arteriopathy. Stroke. 2005;36:1053–1058. doi: 10.1161/01.STR.0000163080.82766.eb. [DOI] [PubMed] [Google Scholar]
- Ayata C. CADASIL: experimental insights from animal models. Stroke. 2010;41:S129–S134. doi: 10.1161/STROKEAHA.110.595207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Joutel A, Monet-Lepretre M, Gosele C, Baron-Menguy C, Hammes A, Schmidt S, et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest. 2010;120:433–445. doi: 10.1172/JCI39733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- el Azzouzi H, van Oort RJ, van der Nagel R, Sluiter W, Bergmann MW, De Windt LJ. MEF2 transcriptional activity maintains mitochondrial adaptation in cardiac pressure overload. Eur J Heart Fail. 2010;12:4–12. doi: 10.1093/eurjhf/hfp165. [DOI] [PubMed] [Google Scholar]
- Mahley RW, Huang Y. Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron. 2012;76:871–885. doi: 10.1016/j.neuron.2012.11.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ostergaard L, Aamand R, Gutierrez-Jimenez E, Ho YC, Blicher JU, Madsen SM, et al. The capillary dysfunction hypothesis of Alzheimer's disease. Neurobiol Aging. 2012;34:1018–1031. doi: 10.1016/j.neurobiolaging.2012.09.011. [DOI] [PubMed] [Google Scholar]
- de la Torre JC. Pathophysiology of neuronal energy crisis in Alzheimer's disease. Neurodegener Dis. 2008;5:126–132. doi: 10.1159/000113681. [DOI] [PubMed] [Google Scholar]
- Desmond DW. The neuropsychology of vascular cognitive impairment: is there a specific cognitive deficit. J Neurol Sci. 2004;226:3–7. doi: 10.1016/j.jns.2004.09.002. [DOI] [PubMed] [Google Scholar]
- Voss SE, Bullock RA. Executive function: the core feature of dementia. Dement Geriatr Cogn Disord. 2004;18:207–216. doi: 10.1159/000079202. [DOI] [PubMed] [Google Scholar]
- Muir ER, Shen Q, Duong TQ. Cerebral blood flow MRI in mice using the cardiac-spin-labeling technique. Magn Reson Med. 2008;60:744–748. doi: 10.1002/mrm.21721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Apostolova I, Wunder A, Dirnagl U, Michel R, Stemmer N, Lukas M, et al. Brain perfusion SPECT in the mouse: normal pattern according to gender and age. NeuroImage. 2012;63:1807–1817. doi: 10.1016/j.neuroimage.2012.08.038. [DOI] [PubMed] [Google Scholar]
- Ayata C, Dunn AK, Gursoy OY, Huang Z, Boas DA, Moskowitz MA. Laser speckle flowmetry for the study of cerebrovascular physiology in normal and ischemic mouse cortex. J Cereb Blood Flow Metab. 2004;24:744–755. doi: 10.1097/01.WCB.0000122745.72175.D5. [DOI] [PubMed] [Google Scholar]
- Adam JF, Elleaume H, Le Duc G, Corde S, Charvet AM, Tropres I, et al. Absolute cerebral blood volume and blood flow measurements based on synchrotron radiation quantitative computed tomography. J Cereb Blood Flow Metab. 2003;23:499–512. doi: 10.1097/01.WCB.0000050063.57184.3C. [DOI] [PubMed] [Google Scholar]
- Shang Y, Chen L, Toborek M, Yu G. Diffuse optical monitoring of repeated cerebral ischemia in mice. Opt Express. 2011;19:20301–20315. doi: 10.1364/OE.19.020301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shih AY, Driscoll JD, Drew PJ, Nishimura N, Schaffer CB, Kleinfeld D. Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain. J Cereb Blood Flow Metab. 2012;32:1277–1309. doi: 10.1038/jcbfm.2011.196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holland PR, Bastin ME, Jansen MA, Merrifield GD, Coltman RB, Scott F, et al. MRI is a sensitive marker of subtle white matter pathology in hypoperfused mice. Neurobiol Aging. 2011;32:2325, e1–e6. doi: 10.1016/j.neurobiolaging.2010.11.009. [DOI] [PubMed] [Google Scholar]
- Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129:154–169. doi: 10.1111/j.1365-2567.2009.03225.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stolp HB, Dziegielewska KM. Review: role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol. 2009;35:132–146. doi: 10.1111/j.1365-2990.2008.01005.x. [DOI] [PubMed] [Google Scholar]
- Zhu P, Ren M, Yang C, Hu YX, Ran JM, Yan L. Involvement of RAGE, MAPK and NF-kappaB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes. Exp Dermatol. 2012;21:123–129. doi: 10.1111/j.1600-0625.2011.01408.x. [DOI] [PubMed] [Google Scholar]
- Kim ES, Kim JS, Kim SG, Hwang S, Lee CH, Moon A. Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Galphaq coupling. J Cell Sci. 2011;124:2220–2230. doi: 10.1242/jcs.076794. [DOI] [PubMed] [Google Scholar]
- Kida K, Minamishima S, Wang H, Ren J, Yigitkanli K, Nozari A, et al. Sodium sulfide prevents water diffusion abnormality in the brain and improves long term outcome after cardiac arrest in mice. Resuscitation. 2012;83:1292–1297. doi: 10.1016/j.resuscitation.2012.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Adair JC, Charlie J, Dencoff JE, Kaye JA, Quinn JF, Camicioli RM, et al. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke. 2004;35:e159–e162. doi: 10.1161/01.STR.0000127420.10990.76. [DOI] [PubMed] [Google Scholar]
- Emanuele E, D'Angelo A, Tomaino C, Binetti G, Ghidoni R, Politi P, et al. Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Arch Neurol. 2005;62:1734–1736. doi: 10.1001/archneur.62.11.1734. [DOI] [PubMed] [Google Scholar]
- Flex A, Gaetani E, Proia AS, Pecorini G, Straface G, Biscetti F, et al. Analysis of functional polymorphisms of metalloproteinase genes in persons with vascular dementia and Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2006;61:1065–1069. doi: 10.1093/gerona/61.10.1065. [DOI] [PubMed] [Google Scholar]
- Rivera S, Khrestchatisky M, Kaczmarek L, Rosenberg GA, Jaworski DM. Metzincin proteases and their inhibitors: foes or friends in nervous system physiology. J Neurosci. 2010;30:15337–15357. doi: 10.1523/JNEUROSCI.3467-10.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huntley GW. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci. 2012;13:743–757. doi: 10.1038/nrn3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, Mercik K, et al. Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J Cell Sci. 2011;124:3369–3380. doi: 10.1242/jcs.090852. [DOI] [PubMed] [Google Scholar]
- Badaut J, Copin JC, Fukuda AM, Gasche Y, Schaller K, da Silva RF. Increase of arginase activity in old apolipoprotein E deficient mice under Western diet associated with changes in neurovascular unit. J Neuroinflamm. 2012;9:132. doi: 10.1186/1742-2094-9-132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bugnicourt JM, Da Silveira C, Bengrine A, Godefroy O, Baumbach G, Sevestre H, et al. Chronic renal failure alters endothelial function in cerebral circulation in mice. Am J Physiol Heart Circ Physiol. 2011;301:H1143–H1152. doi: 10.1152/ajpheart.01237.2010. [DOI] [PubMed] [Google Scholar]
- Kitayama J, Faraci FM, Lentz SR, Heistad DD. Cerebral vascular dysfunction during hypercholesterolemia. Stroke. 2007;38:2136–2141. doi: 10.1161/STROKEAHA.107.481879. [DOI] [PubMed] [Google Scholar]
- Yamashiro K, Milsom AB, Duchene J, Panayiotou C, Urabe T, Hattori N, et al. Alterations in nitric oxide and endothelin-1 bioactivity underlie cerebrovascular dysfunction in ApoE-deficient mice. J Cereb Blood Flow Metab. 2010;30:1494–1503. doi: 10.1038/jcbfm.2010.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lynch JR, Pineda JA, Morgan D, Zhang L, Warner DS, Benveniste H, et al. Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema. Ann Neurol. 2002;51:113–117. doi: 10.1002/ana.10098. [DOI] [PubMed] [Google Scholar]
- McDaniel B, Sheng H, Warner DS, Hedlund LW, Benveniste H. Tracking brain volume changes in C57BL/6J and ApoE-deficient mice in a model of neurodegeneration: a 5-week longitudinal micro-MRI study. NeuroImage. 2001;14:1244–1255. doi: 10.1006/nimg.2001.0934. [DOI] [PubMed] [Google Scholar]
- Anderson R, Barnes JC, Bliss TV, Cain DP, Cambon K, Davies HA, et al. Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse. Neuroscience. 1998;85:93–110. doi: 10.1016/s0306-4522(97)00598-8. [DOI] [PubMed] [Google Scholar]
- Fagan AM, Murphy BA, Patel SN, Kilbridge JF, Mobley WC, Bu G, et al. Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury. Exp Neurol. 1998;151:314–325. doi: 10.1006/exnr.1998.6818. [DOI] [PubMed] [Google Scholar]
- Rahman A, Akterin S, Flores-Morales A, Crisby M, Kivipelto M, Schultzberg M, et al. High cholesterol diet induces tau hyperphosphorylation in apolipoprotein E deficient mice. FEBS Lett. 2005;579:6411–6416. doi: 10.1016/j.febslet.2005.10.024. [DOI] [PubMed] [Google Scholar]
- Grootendorst J, de Kloet ER, Vossen C, Dalm S, Oitzl MS. Repeated exposure to rats has persistent genotype-dependent effects on learning and locomotor activity of apolipoprotein E knockout and C57Bl/6 mice. Behav Brain Res. 2001;125:249–259. doi: 10.1016/s0166-4328(01)00294-7. [DOI] [PubMed] [Google Scholar]
- Xi L, Ghosh S, Wang X, Das A, Anderson FP, Kukreja RC. Hypercholesterolemia enhances tolerance to lethal systemic hypoxia in middle-aged mice: possible role of VEGF downregulation in brain. Mol Cell Biochem. 2006;291:205–211. doi: 10.1007/s11010-006-9194-7. [DOI] [PubMed] [Google Scholar]
- Yi CX, Al-Massadi O, Donelan E, Lehti M, Weber J, Ress C, et al. Exercise protects against high-fat diet-induced hypothalamic inflammation. Physiol Behav. 2012;106:485–490. doi: 10.1016/j.physbeh.2012.03.021. [DOI] [PubMed] [Google Scholar]
- Moreira EL, de Oliveira J, Nunes JC, Santos DB, Nunes FC, Vieira DS, et al. Age-related cognitive decline in hypercholesterolemic LDL receptor knockout mice (LDLr−/−): evidence of antioxidant imbalance and increased acetylcholinesterase activity in the prefrontal cortex. J Alzheimers Dis. 2012;32:495–511. doi: 10.3233/JAD-2012-120541. [DOI] [PubMed] [Google Scholar]
- Norman GJ, Karelina K, Berntson GG, Morris JS, Zhang N, Devries AC. Heart rate variability predicts cell death and inflammatory responses to global cerebral ischemia. Front Physiol. 2012;3:131. doi: 10.3389/fphys.2012.00131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okada S, Yokoyama M, Toko H, Tateno K, Moriya J, Shimizu I, et al. Brain-derived neurotrophic factor protects against cardiac dysfunction after myocardial infarction via a central nervous system-mediated pathway. Arterioscler Thromb Vasc Biol. 2012;32:1902–1909. doi: 10.1161/ATVBAHA.112.248930. [DOI] [PubMed] [Google Scholar]
- Yoshizaki K, Adachi K, Kataoka S, Watanabe A, Tabira T, Takahashi K, et al. Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice. Exp Neurol. 2008;210:585–591. doi: 10.1016/j.expneurol.2007.12.005. [DOI] [PubMed] [Google Scholar]
- Lee JS, Im DS, An YS, Hong JM, Gwag BJ, Joo IS. Chronic cerebral hypoperfusion in a mouse model of Alzheimer's disease: an additional contributing factor of cognitive impairment. Neurosci Lett. 2011;489:84–88. doi: 10.1016/j.neulet.2010.11.071. [DOI] [PubMed] [Google Scholar]
- Kitagawa K, Yagita Y, Sasaki T, Sugiura S, Omura-Matsuoka E, Mabuchi T, et al. Chronic mild reduction of cerebral perfusion pressure induces ischemic tolerance in focal cerebral ischemia. Stroke. 2005;36:2270–2274. doi: 10.1161/01.STR.0000181075.77897.0e. [DOI] [PubMed] [Google Scholar]
- Ma J, Xiong JY, Hou WW, Yan HJ, Sun Y, Huang SW, et al. Protective effect of carnosine on subcortical ischemic vascular dementia in mice. CNS Neurosci Ther. 2012;18:745–753. doi: 10.1111/j.1755-5949.2012.00362.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pimentel-Coelho PM, Michaud JP, Rivest S. Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice. Neurobiol Aging. 2013;34:679–693. doi: 10.1016/j.neurobiolaging.2012.06.025. [DOI] [PubMed] [Google Scholar]
- Reimer MM, McQueen J, Searcy L, Scullion G, Zonta B, Desmazieres A, et al. Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J Neurosci. 2011;31:18185–18194. doi: 10.1523/JNEUROSCI.4936-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.