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. Author manuscript; available in PMC: 2015 Sep 11.
Published in final edited form as: J Alzheimers Dis. 2014;38(3):621–632. doi: 10.3233/JAD-130758

Cerebral microvascular rather than parenchymal amyloid β-protein pathology promotes early cognitive impairment in transgenic mice

WenJin Xu a, Feng Xu b, Maria E Anderson a, AnnMarie E Kotarba b, Judianne Davis b, John K Robinson a, William E Van Nostrand b,*
PMCID: PMC4566953  NIHMSID: NIHMS716819  PMID: 24037035

Abstract

Alzheimer’s disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. The levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits, which suggests other factors such as location of deposition may be more important. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental amyloid deposition, to assess the impact of their respective pathologies on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory and quantitative Aβ pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest that early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits. Key words: amyloid β protein; cerebral microvascular, parenchymal, pathology, cognitive impairment, transgenic mice

Keywords: amyloid β protein, cerebral microvascular, parenchymal, pathology, cognitive impairment, transgenic mice

INTRODUCTION

Alzheimer’s disease (AD), a neurodegenerative disorder and leading cause of dementia, is pathologically characterized by accumulation of extracellular amyloid βprotein (Aβ) deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein [1,2]. In AD, Aβ deposition occurs as parenchymal plaques and in cerebral blood vessels, the latter condition known as cerebral amyloid angiopathy (CAA). Although some studies have found a correlational relationship between cerebral Aβ levels and dementia in AD [3–8], others have reported that the amount of Aβ levels alone are not a reliable predictor of cognitive deficits [9–12]. This suggests that subtle aspects associated with Aβ, such as its specific compartmental accumulation, may be more important determinants related to the onset of dementia. There is evidence that both parenchymal and cerebral microvascular Aβ deposition can promote neuroinflammation and cognitive deficits in patients with AD and related disorders [13–17]. However, emerging studies have underscored the importance of cerebral vascular disease, including CAA, as a potential early driver of cognitive impairment independent of parenchymal Aβ pathology [18–26]. Yet, it is not known how the specific accumulation of Aβ in the cerebral microvascular and the parenchymal compartments temporally contributes to the cognitive decline in patients.

Transgenic mice that specifically develop cerebral microvascular or parenchymal amyloid deposition provide an opportunity to address the contribution of each pathological feature to cognitive impairment. On the one hand, Tg-SwDI mice, a model of early-onset and extensive cerebral microvascular Aβ deposition, have shown that capillary amyloid formation and associated neuroinflammation is intimately linked to behavioral impairments [27–29]. On the other hand, Tg-5xFAD mice, a model of early-onset and robust parenchymal amyloid accumulation exhibit plaque-associated neuroinflammation and develop early behavioral impairments [30–32]. Although both of these distinct transgenic mouse models have been shown to develop impairments in spatial learning and memory tasks the comparative timing of these deficits and their relationship to their respective Aβ pathologies is poorly understood.

Here for the first time, we employed cohorts of these two transgenic lines in parallel to determine the onset of behavioral deficits and the relationship of the deficits to the levels of Aβ, soluble Aβ oligomers and the spatial accumulation of fibrillar amyloid. At three months of age Tg-SwDI mice with the onset of cerebral microvascular amyloid, but not Tg-5xFAD mice with the onset of parenchymal amyloid, exhibited deficits in spatial learning memory despite having much lower levels of total Aβ, soluble oligomeric Aβ, and overall fibrillar amyloid deposition.

MATERIALS AND METHODS

Animals

All work with mice followed National Institutes of Health guidelines and was approved by the Stony Brook University Institutional Animal Care and Use Committee (IACUC). Tg-SwDI mice were generated and characterized in our laboratory as previously described [27–29]. Tg-SwDI mice express the human Swedish/Dutch/Iowa AβPP transgene in neurons under control of the Thy1 promoter element and develop early-onset Aβ deposition and cerebral microvascular amyloid accumulation in the cortex, thalamus and subiculum. Tg-5xFAD mice were obtained from Jackson Laboratories. Tg-5xFAD mice express the human Swedish/Indiana mutant AβPP transgene in neurons also under control of the Thy1 promoter element and develop early-onset Aβ deposition and, in this case, parenchymal plaque amyloid accumulation in the cortex, thalamus and subiculum [30]. Six to eight heterozygous Tg-SwDI, heterozygous Tg-5xFAD, and wild-type mice were used for each 3 and 6 month timepoints.

Behavioral testing

Barnes maze testing was performed as described [29]. Briefly, the Barnes Maze apparatus, originally developed for rats [33], consisted of a sealed wooden disk 91 cm in diameter, elevated 75 cm off the floor, with eight escape holes, spaced 24.5 cm apart. An escape box measuring 10 cm × 8.5 cm × 4 cm was used. Visible distal cues were placed around the room and remained constant throughout each day of testing. Each mouse was given 2 trials per day with a 15 min inter-trial interval. Testing spanned 5 consecutive days. An observer sat 1.5 m away from the maze during trials. At the start of each trial, each mouse was picked up from their home cages by the base of their tail and placed onto the center of the maze. A timer was then started and the mouse was allowed a maximum of 5 min to find a randomized designated hole and escape box. When the mouse entered the box, the timer was stopped and they were given 1 min inside the box before being transferred back to the home cage. If the mouse did not find the escape hole within the 5 min limit, they were picked up by the base of their tail and placed into the hole and left there for 1 minute. The animals were also assessed in the wire hang, rotorod, light/dark box, 0-maze and digiscan activity monitor as previously described [29], following testing in the Barnes maze (data not shown).

Tissue preparation

Mice were overdosed with 2.5% avertin and intracardially perfused with PBS and the brains were removed and bisected along the midsagittal plaine. One hemisphere was snap frozen and used for ELISA and protein analysis. The other hemisphere was placed in 70% ethanol, followed by xylene treatment and embedding in paraffin for immunohistochemical and histological analyses as described [27–29].

Immunochemical analysis of cerebral Aβ peptides

The pools of Aβ40 and Aβ42 were determined by using a specific ELISA as previously described [34,35]. Briefly, soluble Aβ40 and Aβ42 levels were determined in mouse forebrain tissues extracted with 0.1 M sodium carbonate, 0.05 M NaCl, pH 11.5 containing protease inhibitor cocktail. The insoluble Aβ40 and Aβ42 levels were determined in the insoluble pellets resulting from the carbonate extracted brain tissues that were subsequently extracted with 5 M guanidine-HCl. In the sandwich ELISAs, Aβ40 and Aβ42 were captured using their respective carboxyl terminus-specific antibodies m2G3 and m21F12, and biotinylated antibody m3D6, specific for human Aβ, was used for detection [27,28,34,35]. Total Aβ40 and Aβ42 levels were determined by combining the soluble and insoluble levels of each form.

To determine the relative levels of soluble Aβ oligomers the soluble brain fractions prepared above were analyzed by two different methods. First, a sandwich ELISA was performed using m3D6 to capture Aβ species and biotinylated m3D6 for detection of any sized oligomer [35,36]. Alternatively, soluble Aβ oligomers were analyzed by quantitative dot blot analysis using the polyclonal anti-oligomer antibody OC11 as described [30].

Immunohistochemical analysis

Immunohistochemistry was performed as previously described [27–29,37]. Briefly, paraffin sections were cut in the sagittal plane at 10 mm thickness using a microtome. Slides were deparaffinized by immersing in xylene and rehydrated with decreasing concentrations of ethanol. Antigen retrieval was conducted via 5 min incubation with proteinase K (0.2 mg/ml) at 22° C. Primary affinity purified rabbit polyclonal antibody that recognizes residues 1–15 of human Aβ (1:200; [38]) was detected with horseradish peroxidase-conjugated secondary antibody and visualized with a stable diaminobenzidine solution (Life Technologies, Grand Island, NY) as substrate. Sections were counterstained with hematoxylin. Alternatively, deposited fibrillar amyloid was detected with thioflavin-S staining and cerebral vessels were detected with a primary antibody to collagen IV (1:100, Research Diagnostics Inc., Flanders, NJ) and an Alexa Fluor 594-conjugated secondary antibody. Histological images were captured with an Olympus DP72 camera attached to an Olympus BX60 microscope and a Dell desktop computer.

Quantitative analysis of regional Aβ deposition and microvascular CAA

Total Aβ and fibrillar amyloid burden in the regions of the cortex, thalamus and subiculum was respectively quantified on the same set of systematically sampled immunostained or thioflavin-S stained sections, respectively, using NIH image J 1.32 software. The percentage of thioflavin-S labeled blood vessels in the same fields as above was determined with using stereological principles as described [39].

Statistical analyses

All biochemical and pathological data were compared between Tg-SwDI mice and Tg-5xFAD mice using t test with significance considered at p < 0.05. Repeated measures ANOVAs were used to analyze data in the Barnes maze.

RESULTS

Selection of mouse models

In the present study we sought to determine the onset of cognitive impairments associated with either cerebral microvascular amyloid pathology or parenchymal amyloid pathology using two distinct human AβPP transgenic mouse models: Tg-SwDI and Tg-5xFAD, respectively. These models were chosen for several compelling reasons. First, both models express human AβPP under control of the Thy1 promoter and, therefore, produce AβPP and Aβ peptides in the same sets of neurons in brain [22,25]. Second, Tg-SwDI and Tg-5xFAD mice develop their respective pathologies in similar neuroanatomical regions: cortex, thalamus, subiculum, and hippocampus. Lastly, there is a similar onset of about two to three months of age for the respective pathologies in each model. Together, these features of Tg-SwDI mice and Tg-5xFAD mice provide an excellent opportunity to longitudinally compare the onset and extent of cerebral microvascular amyloid pathology or parenchymal amyloid pathology as it relates to the onset of cognitive impairment.

Early cognitive impairments in Tg-SwDI mice but not Tg-5xFAD mice

The findings from the behavioral experiments are summarized in Fig. 1. Repeated measures ANOVA with genotype and age entered as between subject variables and testing day as a within-subject variable revealed significant main effects of genotype (F(2,33) = 7.3, p < 0.002), age of testing (F(1,33) = 4.8, p < 0.03), and a significant genotype × age interaction (F(2,33) = 5.1, p < 0.01). Inspection of the figure shows that at three months of age Tg-SwDI mice are impaired in escape box acquisition consistent with previous findings [29]. In contrast, Tg-5xFAD mice did not exhibit impaired acquisition of the Barnes maze (the latency to find the hidden escape box) at the three month time point. However, impairment in Barnes maze learning is strikingly evident in Tg-5xFAD mice at six months.

Figure 1. Measurement of cognitive impairments in Tg-SwDI mice and Tg-5xFAD mice.

Figure 1

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Groups of three month old and six month old wild-type mice, Tg-SwDI mice, and Tg-5xFAD mice were tested for spatial learning and memory in the Barnes maze task. Tg-SwDI mice showed impairment at three months and six months whereas impairment was not evident in Tg-5xFAD mice until six months. Data are the mean ± SD of six mice per group. Inline graphic, wild-type mice, 3 months; Inline graphic, Tg-5xFAD mice, 3 months; Inline graphic, Tg-SwDI 3 months; Inline graphic, wild-type mice, 6 months; Inline graphic, Tg-5xFAD mice, six months; Inline graphic, Tg-SwDI mice, 6 months.

Tg-5xFAD mice accumulate higher levels of Aβ compared to Tg-SwDI mice

Since Tg-SwDI mice develop an earlier onset of cognitive impairment than Tg-5xFAD mice we next determined if this was related to amount of Aβ that accumulates in the brains of these mice. ELISA analysis was performed to measure the levels of Aβ40 and Aβ42 in both soluble and insoluble brain fractions. As shown in Fig. 2A, at three months of age Tg-SwDI mice accumulated more Aβ40 than Aβ42 with higher amounts in the insoluble fraction, consistent with previous findings [27,29,36]. In contrast, Tg- 5xFAD mice accumulated higher levels of Aβ42 than Aβ40, consistent with the presence of the FAD-linked I716V and V717I AβPP mutations and M146L and L286V PS1 mutations present in this model [30]. However, the amounts of both Aβ40 and Aβ42 in Tg-5xFAD mice were much higher than in Tg-SwDI mice. Although the amounts of each Aβ peptide sharply increased at six months of age the ratios of Aβ40 and Aβ42 in each respective mouse line remained similar and the disproportionately higher levels in Tg- 5xFAD mice remained evident (Fig. 2B).

Figure 2. Measurements of cerebral Aβ levels in Tg-SwDI mice and Tg-5xFAD mice.

Figure 2

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ELISA measurements for Aβ peptides were performed on forebrain hemispheres from three months old and six months old Tg-SwDI mice and Tg-5xFAD mice. These results showed that the levels of soluble and insoluble Aβ40 and Aβ42 peptides were dramatically higher in Tg-5xFAD mice compared to Tg-SwDI mice. ELISA data shown are mean ± S.D. (n = 8–10 animals per group). *p < 0.0001.

Soluble Aβ oligomers have been implicated as important peptide assemblies that can promote neuronal dysfunction [39–42]. Therefore, we next determined the levels of soluble Aβ oligomers in Tg-SwDI mice and Tg-5xFAD mice using two different techniques. First, we used a sandwich ELISA technique to measure soluble oligomers in the soluble brain fraction [35,36]. Alternatively, we performed quantitative dot blot analysis on soluble brain fractions using the Aβ oligomer-specific antibody OC11 [36,43]. Both of these complimentary approaches revealed that at three months of age Tg-5xFAD mice possessed extremely high levels of soluble Aβ oligomers compared to Tg-SwDI mice (Fig. 3A,B). These same techniques showed that at six months of age the levels of soluble Aβ oligomers increased in both mouse lines but, again, the amounts were markedly higher in Tg-5xFAD mice (Fig. 3C,D). Together, these findings show that at three months of age Tg-5xFAD mice accumulate much higher levels of Aβ and soluble Aβ oligomers compared to Tg-SwDI mice suggesting that these measures are not well correlated with cognitive impairment.

Figure 3. Measurements of cerebral soluble Aβ oligomer levels in Tg-SwDI mice and Tg-5xFAD mice.

Figure 3

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ELISA measurements for Aβ oligomers were performed on the soluble fractions of forebrain hemispheres from three months old (A) and six months old (B) Tg-SwDI mice and Tg-5xFAD mice. ELISA data shown are the mean ± S.D. (n = 8- 10 animals per group). *p < 0.0001. Representative dot blot measurements for Aβ oligomers were performed on the soluble fractions of forebrain hemispheres from three months old (C) and six months old (D) Tg-SwDI mice and Tg-5xFAD mice. These results show that Tg-5xFAD mice have much higher levels of soluble Aβ oligomers compared to Tg-SwDI mice.

Tg-5xFAD mice deposit higher amounts of Aβ compared Tg-SwDI mice

Although the quantitative measures above indicate that Tg-5xFAD mice accumulated much higher amounts of Aβ than Tg-SwDI mice we next determined if there was a different neuroanatomical pattern of total Aβ deposition. At three months of age immunostaining for total Aβ in brain tissue sections showed that Tg-5xFAD mice deposit higher amounts compared to Tg-SwDI mice (Fig. 4), consistent with the ELISA measurements of insoluble Aβ (Fig. 2). Quantitation of regional Aβ deposition showed Tg-5xFAD mice had significantly higher amounts in the cortex and thalamus, although the levels in the subiculum were similar (Fig. 4C). At six months of age it was evident that Aβ deposition increased in both mouse lines although it again was more robust in Tg-5xFAD mice. Quantitation showed that the significantly higher amounts of deposited Aβ in the cortex and thalamus of Tg-5xFAD mice remained although the amount of subicular Aβ was higher in Tg-SwDI mice (Fig. 4F). These results indicate that early on the amount of total Aβ deposition is higher in Tg-5xFAD mice compared to Tg-SwDI mice, but again does not correlate with the onset of cognitive impairment.

Figure 4. Cerebral Aβ deposition in Tg-SwDI mice and Tg-5xFAD mice forebrain tissue.

Figure 4

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Human Aβ deposits were detected by immunostaining (brown) in the forebrain of three months and six months old Tg-SwDI mice (A,D) and Tg-5xFAD mice (B,E). Scale bars = 1 mm. Quantitation of regional Aβ deposition in three months old (C) and six months old (F) Tg-SwDI mice and Tg-5xFAD mice. Data shown are the mean ± S.D. (n = 8 animals per group). *p < 0.0001; **p < 0.0004. These results show that Tg-5xFAD mice higher levels of cerebral Aβ deposition compared to Tg-SwDI mice.

Early-onset cerebral microvascular amyloid accumulation correlates with early cognitive impairment in Tg-SwDI mice

The experiments above focused on the quantitative neuroanatomical distribution of total Aβ deposition (Fig. 4). We next sought to determine the amounts and distribution pattern of deposited fibrillar amyloid in the two mouse lines. Brain tissue sections were stained with thioflavin S to identify fibrillar amyloid and immunolabeled to identify cerebral blood vessels. At three months of age Tg-SwDI mice begin to accumulate fibrillar amyloid that is restricted to the microvessels (Fig. 5A) whereas Tg- 5xFAD mice start to accumulate parenchymal plaque fibrillar amyloid (Fig. 5B). Quantitation of total amyloid deposition shows higher amounts in Tg-5xFAD mice compared to Tg-SwDI mice (Fig. 5C). This reflects that the cerebral microvascular fibrillar amyloid in Tg-SwDI mice presents as small, punctate deposits whereas the parenchymal plaque amyloid deposits in Tg-5xFAD mice are much larger. However, the measurement exclusively of cerebral microvascular amyloid shows that it is absent in Tg-5xFAD mice and is highest in the subiculum region of Tg-SwDI mice (Fig. 4D). Although the total amyloid burden increases in both lines of mice at six months and remains significantly higher in Tg-5xFAD mice, the distribution pattern remains the same with fibrillar amyloid restricted to cerebral microvessels in Tg-SwDI mice and largely parenchymal plaques in Tg-5xFAD mice (Fig. 4E–H). These findings suggest that it is not the total fibrillar amyloid burden, but rather the specific early-onset accumulation of fibrillar cerebral microvascular amyloid that correlates as an early driver of cognitive impairment.

Figure 5. Fibrillar amyloid deposition in Tg-SwDI mice and Tg-5xFAD mice.

Figure 5

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Brain sections from Tg-SwDI mice and Tg-5xFAD mice at three months old (A,B) and six months old (E,F) were stained for fibrillar Aβ using thioflavin-S (green) and immunolabeled for collagen type IV to identify cerebral microvessels (red). Scale bars = 50 µM. These results show that Tg-SwDI mice develop cerebral microvascular fibrillar amyloid whereas Tg-5xFAD mice develop parenchymal fibrillar amyloid plaques. Quantitation of total thioflavin-S positive amyloid load in different brain regions of three months old (C) and six months old (G) Tg-SwDI mice and Tg-5xFAD mice. Data shown are mean ± S.D (n = 8 animals per group). *p < 0.0001. These results show that Tg- 5xFAD mice accumulate higher levels of total fibrillar amyloid. Quantitative stereological estimation of cerebral microvascular amyloid load in different brain regions of three months old (D) and six months old (H) Tg-SwDI mice and Tg-5xFAD mice. Data shown are mean ± S.D (n = 8 animals per group). Only Tg-SwDI mice exhibit cerebral microvascular amyloid.

DISCUSSION

It has been proposed that the accumulation of Aβ in the brain promotes deleterious downstream effects such as neuroinflammation, hyperphosphorylation of tau and neuronal death, which in turn causes the cognitive dysfunction seen in AD [1,2]. However, Aβ can spatially accumulate in the brain as parenchymal plaques or cerebral vascular deposits, both of which can contribute to cognitive impairment. The main objective of the present study was to use, in parallel, two distinct transgenic mouse models of either parenchymal amyloid (Tg-5xFAD) or cerebral microvascular amyloid (Tg-SwDI) deposition to investigate the temporal contribution of each type of pathology to cognitive impairment. Contrary to a simple positive relationship between increasing levels of total Aβ, soluble oligomeric Aβ, or deposited Aβ, our data suggest that the site of fibrillar Aβ accumulation may be a more important causal factor in the initial cognitive decline in these animals, and perhaps also in AD patients. Our findings show that overall Aβ levels, while associated with cognitive deficits when reaching extremely high levels, do not have a particularly strong correlation with emerging cognitive decline. While Tg-5xFAD mice exhibited much higher levels of both soluble and insoluble Aβ40 and Aβ42 peptides, as well as soluble Aβ oligomers, in both the three and six month age groups compared to Tg-SwDI mice, they were largely unimpaired in the Barnes maze learning task at the earlier age. These observations point to the importance of the spatial deposition of Aβ as another significant factor in promoting cognitive decline. Indeed, Tg-5xFAD mice and Tg-SwDI mice had markedly distinct parenchymal amyloid versus microvascular amyloid deposition patterns, respectively.

Our data show a striking difference between the Tg-5xFAD and Tg-SwDI strains regarding the amount of accumulated Aβ. At three months or six months of age Tg-5xFAD mice accumulate much more total Aβ than Tg-SwDI mice. Notably, at either age the amount of Aβ42 is ≈6-fold higher than Aβ40 in Tg-5xFAD mice whereas in Tg-SwDI mice it is reversed with the amount of Aβ40 ≈8-fold higher than Aβ42 (Figure 2). Generally, Aβ42 is considered to be more pathogenic due to its stronger ability to assemble into toxic species compared to Aβ40 [1,2,44,45]. However, specific mutations in Aβ, including the Dutch E22Q and Iowa D23N substitutions that are associated with familial forms of CAA [46–48], exhibit greatly enhanced fibrillogenic and pathogenic properties compared to the normal, wild-type forms of Aβ and strongly target cerebral vascular amyloid formation [49–53].

In either case, monomeric Aβ peptides initially aggregate as low molecular mass oligomeric species that adopt progressive β-sheet content to assemble into higher oligomeric forms, protofibrils, and ultimately amyloid fibrils that deposit in cerebral tissues [44,45,54–56]. It is likely that different assemblies of Aβ can promote various pathogenic responses that collectively contribute to the syndrome of AD. For example, different soluble oligomeric species of Aβ are directly toxic to neurons, can interfere with long-term potentiation, and disrupt the integrity of cell membranes [39–42,44,45,56]. On the other hand, fibrillar assemblies of Aβ are toxic to neuronal and cerebral vascular cells, can activate complement, and can stimulate potent neuroinflammatory responses [57–62]. However, we found at either age the amount of soluble Aβ oligomers was vastly higher in Tg-5xFAD mice compared to Tg-SwDI mice. The absence of cognitive impairment in three months old Tg-5xFAD mice indicates that the comparatively high level of soluble Aβ oligomers is not well correlated with the onset of these deficits.

Although the onset of cerebral Aβ deposition occurs on a similar time frame and in the same neuroanatomical regions in Tg-SwDI mice and Tg-5xFAD mice the extent of cerebral Aβ deposition is generally more severe in Tg-5xFAD mice (Fig. 4). Likewise, the amount of fibrillar amyloid deposition is also more severe in Tg-5xFAD mice indicating that total amyloid burden alone does not correlate with early-onset cognitive impairment. However, the compartmental accumulation of fibrillar amyloid is distinct between Tg-5xFAD mice, with its primarily parenchymal plaque deposition, and Tg- SwDI mice, with its cerebral microvascular deposition (Fig. 5). These results indicate that the very high Aβ burden and parenchymal amyloid load seen in Tg-5xFAD mice is insufficient to promote deficits in spatial learning and memory whereas the much lower Aβ levels and focal cerebral microvascular amyloid found in Tg-SwDI mice was adequate to impair performance.

There is growing evidence that vascular-mediated brain injury through ischemic strokes, microbleeds and white matter damage can be early contributing factors to cognitive impairment [63–69]. Certainly microvascular accumulation of amyloid is another form of vascular-mediated brain injury that can have similar deleterious consequences to cognition. In the context of amyloid deposition, previous reports support the idea that the presence of cerebral vascular amyloid is associated with a worse cognitive outcome compared to parenchymal amyloid deposition alone and that this is particularly prominent in the earliest stages of AD related dementia [71–73]. In conclusion, our results show that in transgenic mouse models parenchymal Aβ and amyloid accumulation does not drive cognitive dysfunction until a high threshold is reached whereas cerebral microvascular amyloid has an earlier influence on cognitive decline. Cerebral vascular amyloid and associated pathologies may be more efficacious targets for the onset of amyloid-associated cognitive impairment.

Acknowledgements

This work was supported in part by National Institutes of Health grants RO1-NS55118 and R21-AG33209. Antibody reagents for the Aβ ELISA were generously provided by Lilly Research Laboratories.

REFERENCES

  • 1.Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–766. doi: 10.1152/physrev.2001.81.2.741. [DOI] [PubMed] [Google Scholar]
  • 2.Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. doi: 10.1126/science.1072994. [DOI] [PubMed] [Google Scholar]
  • 3.Cummings BJ, Cotman CW. Image analysis of beta-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet. 1995;346:1524–1528. doi: 10.1016/s0140-6736(95)92053-6. [DOI] [PubMed] [Google Scholar]
  • 4.Haroutunian V, Perl DP, Purohit DP, Marin D, Khan K, Lantz M, Davis KL, Mohs RC. Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol. 1998;55:1185–1191. doi: 10.1001/archneur.55.9.1185. [DOI] [PubMed] [Google Scholar]
  • 5.McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol. 1999;46:860–866. doi: 10.1002/1531-8249(199912)46:6<860::aid-ana8>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  • 6.Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. J Am Med Assoc. 2000;283:1571–1577. doi: 10.1001/jama.283.12.1571. [DOI] [PubMed] [Google Scholar]
  • 7.Parvathy S, Davies P, Haroutunian V, Purohit DP, Davis KL, Mohs RC, Park H, Moran TM, Chan JY, Buxbaum JD. Correlation between Abetax-40-, Abetax-42-, and Abetax-43-containing amyloid plaques and cognitive decline. Arch Neurol. 2001;58:2025–2032. doi: 10.1001/archneur.58.12.2025. [DOI] [PubMed] [Google Scholar]
  • 8.Bussiere T, Friend PD, Sadeghi N, Wicinski B, Lin GI, Bouras C, Giannakopoulos P, Robakis NK, Morrison JH, Perl DP, Hof PR. Stereologic assessment of the total cortical volume occupied by amyloid deposits and its relationship with cognitive status in aging and Alzheimer’s disease. Neuroscience. 2002;112:75–91. doi: 10.1016/s0306-4522(02)00056-8. [DOI] [PubMed] [Google Scholar]
  • 9.Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging. 1991;12:295–312. doi: 10.1016/0197-4580(91)90006-6. [DOI] [PubMed] [Google Scholar]
  • 10.Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42:631–639. doi: 10.1212/wnl.42.3.631. [DOI] [PubMed] [Google Scholar]
  • 11.Berg L, McKeel DW, Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM. Clinicopathologic studies in cognitively healthy aging and Alzheimer’s disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol. 1998;55:326–335. doi: 10.1001/archneur.55.3.326. [DOI] [PubMed] [Google Scholar]
  • 12.Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–1500. doi: 10.1212/01.wnl.0000063311.58879.01. [DOI] [PubMed] [Google Scholar]
  • 13.Nicoll JA, Yamada M, Frackowiak J, Mazur-Kolecka B, Weller RO. Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease Pro-CAA statement. Neurobiol Aging. 2004;25:589–597. doi: 10.1016/j.neurobiolaging.2004.02.003. [DOI] [PubMed] [Google Scholar]
  • 14.Haglund M, Kalaria R, Slade JY, Englund E. Differential deposition of amyloid beta peptides in cerebral amyloid angiopathy associated with Alzheimer’s disease and vascular dementia. Acta Neuropathol. 2006;111:430–435. doi: 10.1007/s00401-006-0054-z. [DOI] [PubMed] [Google Scholar]
  • 15.Eikelenboom P, Veerhuis R, Familian A, Hoozemans JJM, van Gool WA, Rozemuller AJM. Neuroinflammation in plaques and vascular β-amyloid disorders: Clinical and therapeutic implications. Neurodegener Dis. 2008;5:190–193. doi: 10.1159/000113699. [DOI] [PubMed] [Google Scholar]
  • 16.Thal DR, Griffin WST, Braak H. Parenchymal and vascular Aβ-deposition and its effects on the degeneration of neurons and cognition in Alzheimer’s disease. J Cell Mol Med. 2008;12:1848–1862. doi: 10.1111/j.1582-4934.2008.00411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Richard E, Carrano A, Hoozemans JJ, van Horssen J, van Haastert ES, Eurelings LS, de Vries HE, Thal DR, Eikelenboom P, van Gool WA, Rozemuller JM. Characteristics of dyshoric capillary cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2010;69:1158–1167. doi: 10.1097/NEN.0b013e3181fab558. [DOI] [PubMed] [Google Scholar]
  • 18.Natte R, Maat-Schieman ML, Haan J, Bornebroek M, Roos RA, van Duinen SG. Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles. Ann Neurol. 2001;50:765–772. doi: 10.1002/ana.10040. [DOI] [PubMed] [Google Scholar]
  • 19.Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology. 2002;58:1629–1634. doi: 10.1212/wnl.58.11.1629. [DOI] [PubMed] [Google Scholar]
  • 20.Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer’s disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropath Exp Neurol. 2003;62:1287–1301. doi: 10.1093/jnen/62.12.1287. [DOI] [PubMed] [Google Scholar]
  • 21.Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke. 2004;35:2616–2619. doi: 10.1161/01.STR.0000143224.36527.44. [DOI] [PubMed] [Google Scholar]
  • 22.Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurol Res. 2004;26:573–578. doi: 10.1179/016164104225016272. [DOI] [PubMed] [Google Scholar]
  • 23.Haglund M, Sjobeck M, Englund E. Severe cerebral amyloid angiopathy characterizes an underestimated variant of vascular dementia. Dement Geriatr Cogn Disord. 2004;18:132–137. doi: 10.1159/000079192. [DOI] [PubMed] [Google Scholar]
  • 24.Haglund M, Passant U, Sjobeck M, Ghebremedhin E, Englund E. Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia. Int J Geriatr Psychiatry. 2006;21:681–687. doi: 10.1002/gps.1550. [DOI] [PubMed] [Google Scholar]
  • 25.Thal DR, Griffin WS, Braak H. Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. J Cell Mol Med. 2008;12:1848–1862. doi: 10.1111/j.1582-4934.2008.00411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Marchant NL, Reed BR, Sanossian N, Madison CM, Kriger S, Dhada R, Mack WJ, Decarli C, Weiner MW, Mungas DM, Chui HC, Jagust WJ. The aging brain and cognition: contribution of vascular injury and Aβ to mild cognitive dysfunction. JAMA Neurol. 2013;70:488–495. doi: 10.1001/2013.jamaneurol.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral miscrovascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid. J Biol Chem. 2004;279:20296–20306. doi: 10.1074/jbc.M312946200. [DOI] [PubMed] [Google Scholar]
  • 28.Miao J, Xu F, Otte-Höller I, Verbeek MM, Davis J, Van Nostrand WE. Cerebral microvascular Aβ deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant AβPP. Am J Path. 2005;167:505–515. doi: 10.1016/s0002-9440(10)62993-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Xu F, Grande AM, Robinson JK, Previti ML, Davis J, Van Nostrand WE. Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant AβPP transgenic mice. Neuroscience. 2007;146:98–107. doi: 10.1016/j.neuroscience.2007.01.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26:10129–10140. doi: 10.1523/JNEUROSCI.1202-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M, Berry R, Disterhoft JF, Vassar R. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis. 2007;26:134–145. doi: 10.1016/j.nbd.2006.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Ohno M. Failures to reconsolidate memory in a mouse model of Alzheimer’s disease. Neurobiol Learning Memory. 2009;92:455–459. doi: 10.1016/j.nlm.2009.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Barnes CA. Memory deficits associated with senescence: A neuropsychological and behavioral study in the rat. J Comp Physiol Psychol. 1979;93:74–104. doi: 10.1037/h0077579. [DOI] [PubMed] [Google Scholar]
  • 34.Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, Lieberburg I, Schenk D, Seubert P, McConlogue L. Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 1997;94:1550–1555. doi: 10.1073/pnas.94.4.1550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.DeMattos RB, O'dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, Paul SM, Aronow BJ, Holtzman DM. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2002;99:10843–10848. doi: 10.1073/pnas.162228299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Yang T, Hong S, O’Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not in CSF. Alzheimer’s & Dementia. 2013;9:99–112. doi: 10.1016/j.jalz.2012.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 2007;27:3057–3063. doi: 10.1523/JNEUROSCI.4371-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Davis-Salinas J, Saparito-Irwin SM, Donovan FM, Cunningham DD, Van Nostrand WE. Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid β-protein precursor. J Biol Chem. 1994;269:22623–22627. [PubMed] [Google Scholar]
  • 38.Long JM, Kalehua AN, Muth NJ, Calhoun ME, Jucker M, Hengemihle JM, Ingram DK, Mouton PR. Stereological estimation of total microglia number in mouse hippocampus. J Neurosci Meth. 1998;84:101–108. doi: 10.1016/s0165-0270(98)00100-9. [DOI] [PubMed] [Google Scholar]
  • 39.Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–539. doi: 10.1038/416535a. [DOI] [PubMed] [Google Scholar]
  • 40.De Felice FG, Viera MNN, Saraiva LM, Figueroa-Villar JD, Garci-Abreu J, Liu R, Chang L, Klein WL, Ferreira ST. Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aβ oligomerization. FASEB J. 2004;18:1366–1372. doi: 10.1096/fj.04-1764com. [DOI] [PubMed] [Google Scholar]
  • 41.Glabe CG. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging. 2006;27:570–575. doi: 10.1016/j.neurobiolaging.2005.04.017. [DOI] [PubMed] [Google Scholar]
  • 42.Ono K, Condron MM, Teplow DB. Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci USA. 2009;106:14745–14750. doi: 10.1073/pnas.0905127106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener. 2007;2:18. doi: 10.1186/1750-1326-2-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.De Felice FG, Viera MNN, Saraiva LM, Figueroa-Villar JD, Garci-Abreu J, Liu R, Chang L, Klein WL, Ferreira ST. Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aβ oligomerization. FASEB J. 2004;18:1366–1372. doi: 10.1096/fj.04-1764com. [DOI] [PubMed] [Google Scholar]
  • 45.Findeis MA. The role of amyloid beta peptide 42 in Alzheimer's disease. Pharmacol Ther. 2007;116:266–286. doi: 10.1016/j.pharmthera.2007.06.006. [DOI] [PubMed] [Google Scholar]
  • 46.Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248:1124–1126. doi: 10.1126/science.2111584. [DOI] [PubMed] [Google Scholar]
  • 47.Van Broeckhoven C, Haan J, Bakker E, Hardy JA, Van Hul W, Wehnert A, Vegter-Van der Vlis M, Roos RA. Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch) Science. 1990;248:1120–1122. doi: 10.1126/science.1971458. [DOI] [PubMed] [Google Scholar]
  • 48.Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001;49:697–705. doi: 10.1002/ana.1009. [DOI] [PubMed] [Google Scholar]
  • 49.Davis J, Van Nostrand WE. Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. Proc Natl Acad Sci USA. 1996;93:2996–3000. doi: 10.1073/pnas.93.7.2996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE. Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem. 1997;68:1135–1141. doi: 10.1046/j.1471-4159.1997.68031135.x. [DOI] [PubMed] [Google Scholar]
  • 51.Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J. Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000;275:27110–27116. doi: 10.1074/jbc.M003154200. [DOI] [PubMed] [Google Scholar]
  • 52.Melchor JP, McVoy L, Van Nostrand WE. Charge alterations of E22 enhance the pathogenic properties of the amyloid beta-protein. J Neurochem. 2000;74:2209–2212. doi: 10.1046/j.1471-4159.2000.0742209.x. [DOI] [PubMed] [Google Scholar]
  • 53.Van Nostrand WE, Melchor JP, Cho HS, Greenberg SM, Rebeck GW. Pathogenic effects of D23N Iowa mutant amyloid beta-protein. J Biol Chem. 2001;276:32860–32866. doi: 10.1074/jbc.M104135200. [DOI] [PubMed] [Google Scholar]
  • 54.Stine WB, Jr, Dahlgren KN, Krafft GA, LaDu MJ. In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem. 2003;278:11612–11622. doi: 10.1074/jbc.M210207200. [DOI] [PubMed] [Google Scholar]
  • 55.Paravastua AK, Leapman RD, Yau WM, Tycko R. Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils. Proc Natl Acad Sci USA. 2008;105:18349–18354. doi: 10.1073/pnas.0806270105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, Elliott JI, Van Nostrand WE, Smith SO. Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils. Nat Struct Mol Biol. 2010;17:561–567. doi: 10.1038/nsmb.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Urbanc B, Cruz J, Le R, Sanders J, Hsiao Ashe K, Duff K, Stanley HE, Irizarry MC, Hyman BT. Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease. Proc Natl Acad Sci USA. 2002;99:13990–13995. doi: 10.1073/pnas.222433299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Van Nostrand WE, Melchor J, Ruffini L. Pathogenic cell surface amyloid β-protein fibril assembly in cultured human cerebrovascular smooth muscle cells. J Neurochem. 1998;70:216–223. doi: 10.1046/j.1471-4159.1998.70010216.x. [DOI] [PubMed] [Google Scholar]
  • 59.Rogers J, Cooper NR, Webster S, Schulz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Lieberburg I. Complement activation by β-amyloid in Alzheimer's disease. Proc Natl Acad Sci USA. 1992;89:10016–10020. doi: 10.1073/pnas.89.21.10016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Tacnet-Delorme P, Chevallier S, Arlaud GJ. β-amyloid fibrils activate the C1 complex of complement under physiological conditions: Evidence for a binding site for Aβ on the C1q globular regions. J Immunol. 2001;167:6374–6381. doi: 10.4049/jimmunol.167.11.6374. [DOI] [PubMed] [Google Scholar]
  • 61.Rozemuller AJ, van Gool WA, Eikelenboom P. The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer’s disease: therapeutic implications. Curr Drug Targets CNS Neurol Disord. 2005;4:223–233. doi: 10.2174/1568007054038229. [DOI] [PubMed] [Google Scholar]
  • 62.Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and are required for fibrillar Aβ-stimulated microglial activation. J Neurosci. 2009;29:11982–11992. doi: 10.1523/JNEUROSCI.3158-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Werring DJ, Gregoire SM, Cipolotti L. Cerebral microbleeds and vascular cognitive impairment. J Neurol Sci. 2010;299:131–135. doi: 10.1016/j.jns.2010.08.034. [DOI] [PubMed] [Google Scholar]
  • 64.Pluta R, Ulamek M, Jablonski M. Consideration of the ischaemic basis and treatment of Alzheimer’s disease. Folia Neuropathol. 2010;48:11–26. [PubMed] [Google Scholar]
  • 65.Hedden T, Mormino EC, Amariglio RE, Younger AP, Schultz AP, Becker JA, Buckner RL, Johnson KA, Sperling RA, Rentz DM. Cognitive profile of amyloid burden and white matter hyperintensities in cognitively normal older adults. J Neurosci. 2012;32:16233–16242. doi: 10.1523/JNEUROSCI.2462-12.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Marchant NL, Reed BR, DeCarli CS, Madison CM, Weiner MW, Chui HC, Jagust WJ. Cerebrovascular disease, β-amyloid, and cognition in aging. Neurobiol Aging. 2012;33:25–36. doi: 10.1016/j.neurobiolaging.2011.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Zhang M, Chen M, Wang Q, Yun W, Zhang Z, Yin Q, Huang Q, Zhu W. Relationship between cerebral microbleeds and cognitive function in lacunar infarct. J Intl Med Res. 2013;41:347–355. doi: 10.1177/0300060513476448. [DOI] [PubMed] [Google Scholar]
  • 68.Marchant NL, Reed BR, Sanossian N, Madison CM, Kriger S, Dhada R, Mack WJ, DeCarli C, Weiner MW, Mungas DM, Chui HC, Jagust WJ. The aging brain and cognition: contribution of vascular injury and aβ to mild cognitive dysfunction. JAMA Neurol. 2013;70:488–495. doi: 10.1001/2013.jamaneurol.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Provenzano FA, Muraskin J, Tosto G, Narkhede A, Wasserman BT, Griffith EY, Guzman VA, Meier IB, Zimmerman ME, Brickman AM Alzheimer’s Disease Neuroimaging Initiative. White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer’s disease? JAMA Neurol. 2013;70:455–461. doi: 10.1001/jamaneurol.2013.1321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet. 2001;357:169–175. doi: 10.1016/s0140-6736(00)03589-3. [DOI] [PubMed] [Google Scholar]
  • 71.Pfeifer LA, White LR, Ross GW, Petrovitch H, Launer LJ. Cerebral amyloid angiopathy and cognitive function. Neurology. 2002;58:1629–1634. doi: 10.1212/wnl.58.11.1629. [DOI] [PubMed] [Google Scholar]
  • 72.Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer’s disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropath Exp Neurol. 2003;62:1287–1301. doi: 10.1093/jnen/62.12.1287. [DOI] [PubMed] [Google Scholar]
  • 73.Attems J, Jellinger KA. Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study. Acta Neuropathol. 2004;107:83–90. doi: 10.1007/s00401-003-0796-9. [DOI] [PubMed] [Google Scholar]

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