Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 May 3.
Published in final edited form as: Epilepsia. 2012 Nov;53(Suppl 6):45–52. doi: 10.1111/j.1528-1167.2012.03702.x

Inflammatory events at blood–brain barrier in neuroinflammatory and neurodegenerative disorders: Implications for clinical disease

Helga E de Vries *, Gijs Kooij *, Dan Frenkel †, Spiros Georgopoulos ‡, Alon Monsonego §, Damir Janigro
PMCID: PMC4853914  NIHMSID: NIHMS778186  PMID: 23134495

Summary

Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood–brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer’s disease and address potential underlying mechanisms.

Keywords: Epilepsy, Multiple sclerosis, Alzheimer’s disease

The blood–brain barrier (BBB), a unique feature of the cerebral vasculature, closely regulates the exchange of molecules in and out of the brain parenchyma to maintain its proper homeostasis that allows adequate neuronal functioning. An altered function of the BBB has been recognized in various neurologic disorders including multiple sclerosis (MS), stroke, traumatic brain injury (TBI), epilepsy, Alzheimer’s disease, and vascular cognitive impairment. However, to date it remains unclear whether BBB dysfunction is an underlying mechanism for the manifestation of such brain pathologies. While in stroke and TBI, acute BBB dysfunction causes vasogenic edema with the danger of transtentorial herniation, the effects of chronic BBB impairment in neuroinflammatory disorders such as multiple sclerosis (MS) and neurodegenerative disorders such as Alzheimer’s disease and epilepsy are less well understood.

In this review, we briefly recapitulate the role of acute and chronic BBB dysfunction in MS, epilepsy, and Alzheimer’s disease and relate to the relevance for clinical decision-making and give future perspectives inspired by the lectures and discussions that came up during the meeting “Blood–Brain Barrier Dysfunction in Neurological Disorders: Clinical Studies, Underlying Mechanisms and Therapeutic Implications” in Beer-Sheva, Israel in January 2012.

Multiple Sclerosis

Clinical features, diagnostics, and pathology

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), leading to demyelination and neurodegeneration. CNS damage during MS eventually results in a wide range of neurologic disabilities in patients, afflicting mainly young adults. The current view on MS is that of an autoimmune disorder with a neurodegenerative component, and numerous hypotheses exist on the origin of the observed inflammatory responses leading to neurodegeneration in patients with MS.

Diagnosis of MS is mostly established by magnetic resonance imaging (MRI) when patients display clinical signs of MS. MRI scans reveal multiple inflammatory lesions throughout the known predilection sites in the CNS white matter. Disruptions in the BBB, preceding the formation of new MS lesions (Minagar & Alexander, 2003) can be visualized by the intravenous administration of the heavy metal gadolinium chelate diethylenetriamine pentaacetic acid (Gd-DTPA). The high gadolinium signal in MRI indicates leakiness of the BBB and a possible developing MS lesion (Miller et al., 1998).

Pathologic features of MS are predominantly areas of infiltrated inflammatory cells and demyelination in the CNS white matter (WM). In the cortex and deep gray matter (GM) brain regions, areas of demyelination can be detected in the presence of infiltrating inflammatory cells (Lassmann et al., 2007). Demyelinating lesions are often found in proximity to blood vessels (Noseworthy et al., 2000). Infiltration of inflammatory cells usually localizes perivascularly, but can also be seen diffusely in the CNS parenchyma. In acute inflammatory lesions, mainly CD4+ and CD8+ T cells and B cells infiltrate the lesion site. Active (demyelinating) lesions in a later stage show an abundance of macrophages with internalized myelin-degradation products and reactive proliferating astrocytes (Hafler et al., 2005).

The blood–brain barrier in MS and EAE

In MS and its validated animal model experimental allergic encephalomyelitis (EAE), numerous changes in BBB structure and functioning have been described. These observations, derived from in vitro, in vivo animal models, and patient tissue studies, show a high involvement of the disruption of BBB integrity and function in MS pathology. Alterations not only involve the alterations of the tight junction but also include a reduced expression of the efflux pumps, the ATP binding cassette transporters (Kooij et al., 2011). For example, brain endothelial cells downregulate the activity of P-glycoprotein (Pgp), one of the ABC transporters, upon the interaction with activated T cells (Kooij et al., 2010). Together these studies have led to the notion that BBB disruption represents an early event in MS lesion formation, preceding the massive infiltration of leukocytes (mainly T lymphocytes and monocytes-derived macrophages) leading to myelin degradation and nervous tissue destruction (Minagar & Alexander, 2003).

Leukocyte trafficking into the CNS

During MS and EAE, leukocytes enter the CNS, thereby forming perivascular lesions. Upon the encounter of the endothelial cells with circulating or brain-derived inflammatory mediators, the endothelial lining becomes inflamed and will express a range of cell adhesion molecules (CAMs), such as activated leukocyte cell adhesion molecule (ALCAM) (Cayrol et al., 2008), intercellular adhesion molecule-1 (ICAM), and vascular cell adhesion molecule (VCAM) (Alvarez et al., 2011), which are highly expressed by the vasculature in MS and EAE lesions. As a first step in the recruitment of leucocytes by endothelia, the interaction of the endothelial and leukocytic surface molecules slows down the circulating immune cells, allowing the attachment of leukocytes to the inflamed endothelium. This loose attachment enables the interaction between the endothelial CAMs and their leukocytic integrins, leading to the firm adhesion of the leukocytes. In turn, this leukocyte–endothelial interaction will initiate a cascade of intracellular signaling events that lead to the transmigration of leukocytes across the endothelia lining (Greenwood et al., 2011).

Based on the adhesion molecule interference studies in animals with EAE, a newly approved drug was developed, Tysabri (natalizumab). This humanized antibody blocks the interaction of the very late antigen-4 (VLA-4) integrin. Currently, Tysabri is reported to diminish the development of new inflammatory lesions in MS and also diminishes BBB leakage as evidenced by Gd-DTPA studies (Polman et al., 2006).

Not only adhesion molecules affect leukocyte trafficking into the CNS. It has been demonstrated that reactive oxygen species (ROS), produced by monocytes upon firm adhesion to endothelial cells (ECs), are able to enhance migration and adhesion of monocytes (Van der Goes et al., 2001). Treatment with the antioxidant luteolin of an acute EAE (acEAE) model suppressed the development of EAE. Histologic examination demonstrated a reduced number of infiltrated T cells and macrophages, suggesting a role for ROS in BBB permeability (Hendriks et al., 2004).

An altered interaction of astrocytes with the endothelial cells may also underlie the process of neuroinflammation in MS. It has been demonstrated that astrocytes become activated and will produce a number of inflammatory mediators such as chemokines, which in turn attract inflammatory cells into the brain parenchyma (Kooij et al., 2011).

Epilepsy

Epilepsy and seizure disorders

Another disorder that involves a dysfunction of the BBB is epilepsy. The occurrence of seizures does not always lead to a diagnosis of epilepsy. Within a life span, 5–10% of the population will have at least one seizure without being considered as epileptic (Shorvon, 2005). Although the distinction between seizures and epilepsies is clinically well understood, a semantic uncertainty still subsists among basic scientists. Epilepsy research has often failed to fully take into account the important lessons learned from clinicians: this sometimes led to a simplistic modeling of the disease. This gap, if bridged, will unveil novel mechanisms and open a venue for the investigation of new therapeutic approaches. Acknowledgment of the differences between seizures and epilepsy has allowed for refining of animal models and also tailoring research efforts toward the reproduction of symptoms (seizures) or the epileptogenic process.

The blood–brain barrier in seizure disorders

The BBB has been recognized as a clinically relevant structure for two primary reasons. On the one hand, it was noted that the BBB is an obstacle to CNS drug delivery, and that strategies to “outwit” the BBB are often necessary for successful treatment (Kroll & Neuwelt, 1998). On the other hand, it was suspected, but until recently not fully appreciated, that loss of BBB shielding can have dramatic consequences for brain function. For example, although the potential role of the BBB in seizure disorders was initially formulated in 1958 (Quadbeck & Helmchen, 1958) it was only recently that BBB disruption has been causatively linked to seizures (Seiffert et al., 2004; Ivens et al., 2007; Marchi et al., 2007a; Uva et al., 2007; van Vliet et al., 2007; Fabene et al. 2008). Perhaps not by coincidence, the epileptogenic consequences of BBB disruption were demonstrated by using the same “outwitting” procedure used to improve drug penetration in the CNS. Therefore, when the “Rapoport-Neuwelt” osmotic BBB disruption protocol (Rapoport et al., 1972; Kroll & Neuwelt, 1998) was used to enhance uptake of cisplatin or methotrexate in brain, focal motor seizures were immediately (within a 2–5 min) apparent (Rapoport et al., 1972; Marchi et al., 2007a; Angelov et al., 2009). A link between BBB disruption and seizures was confirmed by a broad range of experimental approaches, and the conclusion that BBB disruption is neuropathogenic remains unchallenged (Tomkins et al., 2001; Seiffert et al., 2004; Korn et al., 2005; van Vliet et al., 2007; Fabene et al. 2008; David et al., 2009; Marchi et al. 2009; Marchi et al., 2011a,b).

Because BBB disruption is an etiologic mechanism of neurologic disorders, it follows that BBB repair may be also accompanied by improved symptoms. This was recently shown in epilepsy (Marchi et al. 2009; Marchi et al., 2011a), but other diseases are likely to reveal that the BBB is a viable target for therapy. The etiologic role for the BBB and its failure in seizure disorders may suggest overlapping mechanisms with MS. In addition, there are reports of anti-MS drugs that work in seizure patients or models (Fabene et al. 2008; Marchi et al. 2009; Sotgiu et al., 2010; Marchi et al., 2011a). However, clinical reality suggests that the two conditions, although both in part associated with BBB disruption, are significantly different.

The blood–brain barrier in seizure disorders and MS

The pathogenesis of epilepsy is not necessarily identical to the pathogenesis of seizures. This is in sharp contrast with MS, where symptoms correlate with imaging or other clinical diagnostic findings. Seizures occur commonly in individuals without epilepsy, and in persons with epilepsy the frequency and severity of seizures varies greatly among individuals. A peculiarity of seizure disorders is that seizures beget seizures, so that significant brain rewiring induced by a single prolonged episode may lead to epileptogenesis and spontaneous seizures. This has been exploited in many animal models, where status epilepticus is induced by a chemoconvulsive agent such as pilocarpine, and then, after a so-called latent period, spontaneous seizures occur (Fisher, 1989; Cavalheiro et al., 2006). In MS, as well as in animal models of demyelinating disorders, there is no known “causative agent,” and autoimmunity associated with a “leaky” BBB is necessary and sufficient to cause symptoms. These persist or wane based on the type of disease, but symptoms are ameliorated by interventions that improve BBB function and decrease immune activity.

In the epileptic brain, leukocytes are absent and apparently irrelevant for disease progression. This has been shown in animal models, as well as in human brain specimens (Marchi et al., 2011b). Although leukocyte presence in epileptic brain is uncommon, systemic leukocyte activation, often comparable to MS, is a hallmark of seizure activity in patients as well as in animal models (Marchi et al., 2007b; Uva et al., 2007; Bauer et al., 2008; Marchi et al. 2009). There are conflicting reports on the nature of cell types involved, and differences exists between models where convulsive agents are directly injected into the brain, for example, kainic acid (Zattoni et al., 2011), versus models where convulsions are seen after systemic administration, for example, pilocarpine (Fabene et al. 2008; Marchi et al., 2007b; Marchi et al. 2009). The pilocarpine model was recently used to investigate the pattern of white blood cell (WBC) brain extravasations during epileptogenesis and chronic seizures. Granulocytes transiently extravasated in brain during epileptogenesis, whereas monocytes/macrophages were present in the hippocampus until chronic seizures developed. Negligible presence of B and T lymphocytes and natural killer cells was reported (Ravizza et al., 2008). Other studies have demonstrated that pharmacologic prevention of BBB damage was sufficient to reduce the onset of pilocarpine seizures regardless of whether cell entry was observed (Fabene et al. 2008; Marchi et al. 2009). These findings suggest that, at least in this model, WBC extravasation into the brain is not required to generate acute seizures.

How WBCs involved in the generation of abnormal neuronal discharge resulting in seizures get in and out of the brain remains largely unknown. In addition, the topography of cellular (leukocytes) and molecular (serum albumin, ions) leakage is not well understood. It is, for example, not known at what stage and by which mechanisms capillary leakage occurs, and whether sites of cellular and molecular extravasation are the same. The largest surface separating brain from blood is the BBB proper, but several lines of evidence point to postcapillary venules as chief controllers of trans-EC migration in the brain (del Zoppo, 1994; Engelhardt & Ransohoff, 2005; del Zoppo, 2008, 2009). What remains unclear is the role, if any, of extravasated cells. In white matter brain disease and stroke, the role for immune cells has been brilliantly and exhaustively presented in recent reviews (Engelhardt & Ransohoff, 2005; del Zoppo, 2008, 2009). Whether a similar role exists in epilepsy and in general for gray matter diseases will be clarified by experiments taking advantage of modern cell tracking methods.

The neurovascular unit in seizure disorders

Tridirectional communication linking the nervous, endocrine, and immune system has become an extensively investigated scientific area in recent years. Research on this topic has involved almost every relevant human neurologic disease entity. Paroxysmal events due to abnormal, excessive, hypersynchronous discharges from an aggregate of central nervous system neurons occur in epileptic seizures, MS (dyskinesia), after trauma, and after transient-ischemic attacks. Under most circumstances, cerebral blood flow is compromised in these pathologies, often in an age-dependent fashion (e.g., Armstead, 2005; Udomphorn et al., 2008). A surprising overlap between different pathologies has been reported. For example, cell death is a common cause and outcome of a variety of neurologic disorders. Ischemia promotes so-called excitotoxic neuronal death, leading to dramatic and often irreversible loss of function. In seizure disorders, cell death is less dramatic but is also believed to be initiated by excitotoxicity (Bengzon et al., 2002). Neuronal rewiring occurs as a consequence of neuronal cell loss, and this newly formed circuitry is ascribed to the progression of disease (Proper et al., 2000). Recent findings have shown that these two seemingly unrelated pathologies have a common mechanism, namely reduction of rCBF, which may be the trigger for cell death in epilepsy and stroke. Additional communality is found when assessing the role of inflammation in embolic and seizure disorders and when considering that both conditions are characterized by a leaky BBB (e.g., review del Zoppo et al., 2001; Grant & Janigro, 2004; del Zoppo, 2008, 2009; Rosenberg, 2009)).

Alzheimer’s Disease

Alzheimer’s disease and capillary cerebral amyloid angiopathy (cap CAA): pathology

Alzheimer’s disease is the most common type of dementia occurring in the elderly. The main cause of this disease is generally attributed to the increased production and accumulation of amyloid-β (Aβ), as well as neurofibrillary tangle composed of intracellular hyperphosphorylated tau protein, and loss of synapses and neurons. Cerebral amyloid angiopathy (CAA) is defined as the deposition of vascular amyloid in the walls of the meningeal and parenchymal arteries, arterioles, capillaries and, albeit rarely, veins. The vascular amyloid deposits in CAA are composed primarily of the β-amyloid peptide (Aβ), and a number of other molecules, such as extracellular matrix proteins, α1-antichymotrypsin, apolipoprotein E, acetylcholinesterase, and cystatin C, coinciding with glial activation. The prevalence of CAA, estimated from autopsy series, is approximately 10–40% in the general elderly population and almost 80% of cases Alzheimer’s disease.

The role of blood–brain barrier in capillary amyloid angiopathy (cap CAA) and Alzheimer’s disease

Recent evidence indicates that in cases with predominantly capillary CAA, loss of tight junction proteins of the BBB is found in combination with extensive neuroinflammatory events (Carrano et al., 2011, 2012). A number of cerebrovascular abnormalities have been described in Alzheimer’s disease brains, as endothelial and pericyte damage, diminished glucose transport across the BBB, expression of inflammatory markers in the brain vasculature, and microvascular degeneration (Bowman & Quinn, 2008; Zlokovic, 2008; Nagababu et al., 2009). It is difficult to say if these changes are an initial cause for development of Alzheimer’s disease or if these changes occur in late stages of the disease. A high percentage of patients with Alzheimer’s disease exhibit vascular pathology and develop CAA, intracerebral hemorrhage, and cerebral infracts (McCarron & Nicoll, 2004; Nicoll et al., 2004). Amyloid deposits are usually observed both in the larger blood vessels and the smaller cerebral capillaries that make up the BBB. These findings suggest for an impaired mechanism of Aβ clearance at the BBB level in Alzheimer’s disease (Zlokovic, 2004).

Amyloid clearance from the brain: role for the BBB

Because vascular endothelium does not permit passive diffuse of solutes as Aβ between brain and blood, the presence of a transporting mechanism for Aβ on the BBB is suspected. A number of receptors involved in cholesterol metabolism, like the low-density lipoprotein receptor–related (LRP)-1 and the scavenger receptor (SR)-BI, are expressed in the BBB and have been reported to regulate amyloid deposition both in the brain vasculature and parenchyma in Alzheimer’s disease mouse models (Deane et al., 2004; Thanopoulou et al., 2010; Zlokovic et al., 2010).

The LRP, the CD36, and the SR-BI receptors have been implicated in amyloid-related pathology, CAA, and cerebrovascular function in Alzheimer’s disease transgenic mice (Thanopoulou et al., 2010; Zlokovic et al., 2010; Park et al., 2011). LRP is a multifunctional receptor expressed in the brain and involved in Aβ clearance. LRP together with the low density lipoprotein receptor are the key regulators in the trafficking of LDL cholesterol and apolipoprotein E (ApoE)-containing lipoproteins, as they both bind ApoE (Zlokovic et al., 2010; Katsouri & Georgopoulos, 2011). LRP has been shown to play a major role in Aβ transport and clearance at the BBB level. CD36 is a scavenger receptor expressed on brain capillary endothelium that mediates the toxic effect of Aβ in cerebrovascular function in Alzheimer’s disease mice (Park et al., 2011). The scavenger receptor SR-BI, a high density lipoprotein cholesterol receptor, is a major modulator of vascular amyloid deposition and amyloid plaque formation in an Alzheimer’s disease mouse model (Thanopoulou et al., 2010). SR-BI is expressed in the brain vasculature and deletion or reduction of SR-BI, in the SR-BI−/− or +/− mice, results in a massive increase of perivascular macrophages in brain blood vessels. Reduction of SR-BI protein levels in an Alzheimer’s disease transgenic mouse that carries on SR-BI allele (SR-BI+/−), brings a significant increase in CAA and amyloid plaque formation as well as cognitive deficits. Despite the increase of perivascular macrophages, amyloid deposition in the brain vasculature and parenchyma are enhanced, suggesting that SR-BI is involved in Aβ clearance. These findings suggest that cholesterol receptors expressed at the BBB play a major role in Alzheimer’s disease and CAA and are potential targets for therapy.

Role of TGF-β1 in barrier dysfunction in Alzheimer’s disease and CAA

To date, the mechanisms that underlie this altered function of the barrier in Alzheimer’s disease remain elusive, but reports indicate that TGFb1 may play a role in BBB dysfunction in Alzheimer’s disease pathogenesis. Many reports have demonstrated a significant impairment of TGFβ1 signaling in Alzheimer’s disease brain (Tesseur et al., 2006; Caraci et al., 2012) and TGFβ1 has a constitutive role in the suppression of inflammation and appears to control the degree of microglial activation in the CNS (Caraci et al., 2012). The most widely recognized clinical manifestation of CAA is intracerebral hemorrhage (ICH) and cognitive impairment (Greenberg, 2002). Cortical TGFβ1 levels correlate positively with the degree of cerebrovascular amyloid deposition in Alzheimer’s disease cases, and TGFβ1 immunoreactivity was elevated along the cerebral blood vessels (Wyss-Coray et al., 2000). Moreover, in mice, transgenic overexpression of TGFβ1 under the control of an astrocyte glial fibrillary acidic protein (GFAP) promoter causes an age-related deposition of amyloid (starting at 8 months) around cerebral blood vessels and prominent perivascular astrocytosis. Furthermore, these mice have cognitive impairment that may reflect vascular dementia in patients (Lifshitz et al., 2012).

Recent findings support the importance of endothelial cells and macrophage cross-talk in preventing cerebrovascular amyloid depositions (Lifshitz et al., 2012). This cross-talk may be disrupted following pathologic expression of TGFβ1 by astrocytes along the cerebrovascular system (Lifshitz et al., 2012). Changes in endothelial cell–secreted factors following TGFβ1 stimulation leads to a reduction in macrophage activity as measured by protein levels and migration ability (Weiss et al., 2011). Understanding extracellular immune system interactions may pave the way to a new therapeutic approach in cerebrovascular amyloidosis disease such as Alzheimer’s disease (see Kim et al., 2012, this issue).

CAA-driven pathology following Aβ immunization: role of infiltrated leukocytes

A possible therapeutic approach to Alzheimer’s disease was suggested by studies in which amyloid precursor protein (APP)–transgenic (Tg) mice were vaccinated with Aβ emulsified in CFA. Treated mice exhibited reduced plaque formation and reduced gliosis, as well as a slower decline in cognitive deficits, correlated with a high titer of anti-Ab antibodies in the serum (Schenk et al., 1999; Janus et al., 2000; Morgan et al., 2000; Weiner et al., 2000; DeMattos et al., 2001; Maier et al., 2006). However, phase II clinical trials conducted with this vaccine were discontinued when 6% of the vaccinated Alzheimer’s disease patients developed meningoencephalitis (Orgogozo et al., 2003). Postmortem examination revealed T cells primarily in meningeal areas in which Aβ had accumulated (Nicoll et al., 2003), as well as drainage of Aβ to the vasculature (Boche et al., 2008; Holmes et al., 2008). The mechanism of such inflammatory reaction at the brain vasculature and parenchyma upon Aβ immunization has so far remained elusive.

Among the leukocytes accumulating at the vasculature upon Aβ vaccination, primarily CD4 and to a lesser extent CD8+T cells were found to cross the glia limitans and target Aβ plaques within the parenchyma (Monsonego et al., 2006). Data from recent years have shown that such crossing of the glia limitans requires further antigenic stimulation of the T cells at the perivascular space (Serafini et al., 2000; Archambault et al., 2005; Greter et al., 2005; Bartholomaus et al., 2009; Kivisakk et al., 2009). In experimental models for MS, major histocompatibility complex class II expression by perivascular CD11c+ dendritic cells (DCs) is required if encephalitogenic T cells are to enter the CNS (Greter et al., 2005). Our recent findings support a similar mechanism in a mouse model of Alzheimer’s disease expressing limited amounts of interferon γ (IFN-γ) in the CNS. When APP/IFN-γ Tg mice were immunized with Ab, perivascular CD11c+ cells were found on brain microvasculature as well as in the leptomeningeal spaces and were in contact with infiltrating CD4 T cells. Furthermore, CD11c+ cells were only found in areas where Aβ is highly deposited, that is, the hippocampus and the frontal cortex regions. Contrary to this phenomenon, when APP/IFN-γ Tg mice were immunized with proteolipid protein (PLP), an encephalitogenic antigen prevalent in the CNS, however unrelated to AD, CD11c+ cells were found only in areas rich in myelin such as the white matter of the cerebellum and the spinal cord and were essentially absent from grey matter areas such as the cortex and the hippocampus (Fisher et al., 2011).

Our model suggests that following Aβ immunization, Aβ-specific T cells target the brain vasculature in which Aβ is deposited. This homing of Aβ-specific T cells to the perivascular space is presumably triggered by a proinflammatory milieu generated by perivascular macrophages/pericytes at the brain vasculature deposited with Ab. DCs that consequently settle in the perivascular space promote the activation and further accumulation of Aβ-specific T cells and their entry into the parenchyma via the glia limitans.

The role of bone-marrow–derived immune cells and scavenger receptors in Alzheimer’s disease and CAA

Microglia and astrocytes are the immune cells of the brain to be activated first in response to Aβ in the Alzheimer’s disease brain. In addition to these CNS endogenous cells, bone marrow–derived cells that originate from the periphery have been identified in amyloid deposits in the brain. Until recently the role of the peripheral immune cells was believed to be limited, but accumulating evidence has supported a significant role for infiltrating cells from the periphery, in regulating amyloid deposition in Alzheimer’s disease and CAA along with the endogenous astrocytes and microglia (Rezai-Zadeh et al., 2009, 2011). Selective ablation of bone marrow–derived macrophages has a negative effect in amyloid deposition and increases amyloid plaques in Alzheimer’s disease transgenic mice (Butovsky et al., 2007). In addition, blood-derived macrophages from patients with Alzheimer’s disease were shown to be less effective at phagocytosing Aβ compared with cells derived from nondemented control patients (Fiala et al., 2005). Perivascular macrophages, a group of bone marrow–derived macrophages located in blood vessels within the brain, is involved in transporting and clearing Aβ (Hickey & Kimura, 1988; Williams et al., 2001). Depletion of perivascular macrophages significantly increased CAA in Alzheimer’s disease transgenic mice, whereas stimulation of perivascular macrophages turn-over promoted Aβ clearance in the mouse brain, suggesting a dominant role of perivascular macrophages in vascular amyloid deposition (Hawkes & McLaurin, 2009).

Common Denominators

In neurologic disorders such as MS, epilepsy and capillary CAA, and Alzheimer’s disease, a profound dysfunction of the BBB is apparent. Due to the close association of the astrocytic end-feet and the vasculature, the local secretion of permeability inducing mediators may lead to disturbed function of the BBB. However, to date it remains undefined if an altered interaction of reactive astrocytes and endothelial cells contributes to pathogenesis of the mentioned diseases. Future research into the altered communication of active astrocytes and endothelial cells of the BBB is therefore needed.

Moreover, further studies are needed to explore the differential role of infiltrating leukocytes at the vascular and parenchymal brain compartments of the Alzheimer’s disease brain with the aim of designing new immune-based approaches, which ease both the accumulation of Aβ and the associated inflammatory reaction in the brain.

Footnotes

Disclosure

The authors have no conflicts of interest to disclose. The authors we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonniere L, Bernard M, van HJ, de Vries HE, Charron F, Prat A. The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science. 2011;334:1727–1731. doi: 10.1126/science.1206936. [DOI] [PubMed] [Google Scholar]
  2. Angelov L, Doolittle ND, Kraemer DF, Siegal T, Barnett GH, Peereboom DM, Stevens G, McGregor J, Jahnke K, Lacy CA, Hedrick NA, Shalom E, Ference S, Bell S, Sorenson L, Tyson RM, Haluska M, Neuwelt EA. Blood–brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol. 2009;27:3503–3509. doi: 10.1200/JCO.2008.19.3789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Archambault AS, Sim J, Gimenez MA, Russell JH. Defining antigen-dependent stages of T cell migration from the blood to the central nervous system parenchyma. Eur J Immunol. 2005;35:1076–1085. doi: 10.1002/eji.200425864. [DOI] [PubMed] [Google Scholar]
  4. Armstead WM. Age and cerebral circulation. Pathophysiology. 2005;12:5–15. doi: 10.1016/j.pathophys.2005.01.002. [DOI] [PubMed] [Google Scholar]
  5. Bartholomaus I, Kawakami N, Odoardi F, Schlager C, Miljkovic D, Ellwart JW, Klinkert WE, Flugel-Koch C, Issekutz TB, Wekerle H, Flugel A. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009;462:94–98. doi: 10.1038/nature08478. [DOI] [PubMed] [Google Scholar]
  6. Bauer S, Koller M, Cepok S, Todorova-Rudolph A, Nowak M, Nockher WA, Lorenz R, Tackenberg B, Oertel WH, Rosenow F, Hemmer B, Hamer HM. NK and CD4+ T cell changes in blood after seizures in temporal lobe epilepsy. Exp Neurol. 2008;211:370–377. doi: 10.1016/j.expneurol.2008.01.017. [DOI] [PubMed] [Google Scholar]
  7. Bengzon J, Mohapel P, Ekdahl CT, Lindvall O. Neuronal apoptosis after brief and prolonged seizures. Prog Brain Res. 2002;135:111–119. doi: 10.1016/S0079-6123(02)35011-8. [DOI] [PubMed] [Google Scholar]
  8. Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain. 2008;131:3299–3310. doi: 10.1093/brain/awn261. [DOI] [PubMed] [Google Scholar]
  9. Bowman GL, Quinn JF. Alzheimer’s disease and the blood–brain barrier: past, present and future. Aging Health. 2008;4:47–55. doi: 10.2217/1745509X.4.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer’s disease model. Eur J Neurosci. 2007;26:413–416. doi: 10.1111/j.1460-9568.2007.05652.x. [DOI] [PubMed] [Google Scholar]
  11. Caraci F, Spampinato S, Sortino MA, Bosco P, Battaglia G, Bruno V, Drago F, Nicoletti F, Copani A. Dysfunction of TGF-beta1 signaling in Alzheimer’s disease: perspectives for neuroprotection. Cell Tissue Res. 2012;347:291–301. doi: 10.1007/s00441-011-1230-6. [DOI] [PubMed] [Google Scholar]
  12. Carrano A, Hoozemans JJ, van der Vies SM, Rozemuller AJ, van Horssen J, de Vries HE. Amyloid Beta induces oxidative stress-mediated blood–brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal. 2011;15:1167–1178. doi: 10.1089/ars.2011.3895. [DOI] [PubMed] [Google Scholar]
  13. Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ. Neuroinflammation and blood–brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis. 2012;10:329–331. doi: 10.1159/000334916. [DOI] [PubMed] [Google Scholar]
  14. Cavalheiro EA, Naffah-Mazzacoratti MG, Mello LE, Leite JP. The pilocarpine model of seizures. In: Pitkanen A, Schwartzkroin PA, Moshe SL, editors. Models of seizures and epilepsy. Elsevier; New York: 2006. pp. 443–446. [Google Scholar]
  15. Cayrol R, Wosik K, Berard JL, Dodelet-Devillers A, Ifergan I, Kebir H, Haqqani AS, Kreymborg K, Krug S, Moumdjian R, Bouthillier A, Becher B, Arbour N, David S, Stanimirovic D, Prat A. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol. 2008;9:137–145. doi: 10.1038/ni1551. [DOI] [PubMed] [Google Scholar]
  16. David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, Friedman A. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci. 2009;29:10588–10599. doi: 10.1523/JNEUROSCI.2323-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Deane R, Wu Z, Sagare A, Davis J, Du YS, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43:333–344. doi: 10.1016/j.neuron.2004.07.017. [DOI] [PubMed] [Google Scholar]
  18. del Zoppo GJ. Microvascular changes during cerebral ischemia and reperfusion. Cerebrovasc Brain Metab Rev. 1994;6:47–96. [PubMed] [Google Scholar]
  19. del Zoppo GJ. Virchow’s triad: the vascular basis of cerebral injury. Rev Neurol Dis. 2008;5(Suppl. 1):S12–S21. [PMC free article] [PubMed] [Google Scholar]
  20. del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience. 2009;158:972–982. doi: 10.1016/j.neuroscience.2008.08.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol. 2001;58:669–672. doi: 10.1001/archneur.58.4.669. [DOI] [PubMed] [Google Scholar]
  22. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2001;98:8850–8855. doi: 10.1073/pnas.151261398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 2005;26:485–495. doi: 10.1016/j.it.2005.07.004. [DOI] [PubMed] [Google Scholar]
  24. Fabene PF, Navarro MG, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, Zanetti L, Schio F, Osculati A, Marzola P, Nicolato E, Homeister JW, Xia L, Lowe JB, McEver RP, Osculati F, Sbarbati A, Butcher EC, Constantin G. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med. 2008a;14:1377–1383. doi: 10.1038/nm.1878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis. 2005;7:221–232. doi: 10.3233/jad-2005-7304. [DOI] [PubMed] [Google Scholar]
  26. Fisher RS. Animal models of the epilepsies. Brain Res Brain Res Rev. 1989;14:245–278. doi: 10.1016/0165-0173(89)90003-9. [DOI] [PubMed] [Google Scholar]
  27. Fisher Y, Nemirovsky A, Baron R, Monsonego A. Dendritic cells regulate amyloid-beta-specific T-cell entry into the brain: the role of perivascular amyloid-beta. J Alzheimers Dis. 2011;27:99–111. doi: 10.3233/JAD-2011-102034. [DOI] [PubMed] [Google Scholar]
  28. Grant GA, Janigro D. The blood–brain barrier. In: Winn HR, editor. Youmans neurological surgery. Saunders; Philadelphia, PA: 2004. pp. 153–174. [Google Scholar]
  29. Greenberg SM. Cerebral amyloid angiopathy and vessel dysfunction. Cerebrovasc Dis. 2002;13(Suppl. 2):42–47. doi: 10.1159/000049149. [DOI] [PubMed] [Google Scholar]
  30. Greenwood J, Heasman SJ, Alvarez JI, Prat A, Lyck R, Engelhardt B. Review: leucocyte-endothelial cell crosstalk at the blood–brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol. 2011;37:24–39. doi: 10.1111/j.1365-2990.2010.01140.x. [DOI] [PubMed] [Google Scholar]
  31. Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med. 2005;11:328–334. doi: 10.1038/nm1197. [DOI] [PubMed] [Google Scholar]
  32. Hafler DA, Slavik JM, Anderson DE, O’Connor KC, De JP, Baecher-Allan C. Multiple sclerosis. Immunol Rev. 2005;204:208–231. doi: 10.1111/j.0105-2896.2005.00240.x. [DOI] [PubMed] [Google Scholar]
  33. Hawkes CA, McLaurin J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci USA. 2009;106:1261–1266. doi: 10.1073/pnas.0805453106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hendriks JJ, Alblas J, Van Der Pol SM, van Tol EA, Dijkstra CD, de Vries HE. Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med. 2004;200:1667–1672. doi: 10.1084/jem.20040819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hickey WF, Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science. 1988;239:290–292. doi: 10.1126/science.3276004. [DOI] [PubMed] [Google Scholar]
  36. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216–223. doi: 10.1016/S0140-6736(08)61075-2. [DOI] [PubMed] [Google Scholar]
  37. Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain. 2007;130:535–547. doi: 10.1093/brain/awl317. [DOI] [PubMed] [Google Scholar]
  38. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature. 2000;408:979–982. doi: 10.1038/35050110. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D. Blood–brain barrier dysfunction–induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia. 2012;53(Suppl. 6):37–44. doi: 10.1111/j.1528-1167.2012.03701.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, Khoury SJ. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol. 2009;65:457–469. doi: 10.1002/ana.21379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kooij G, van HJ, de Lange EC, Reijerkerk A, Van Der Pol SM, Van Het HB, Drexhage J, Vennegoor A, Killestein J, Scheffer G, Oerlemans R, Scheper R, van der Valk P, Dijkstra CD, de Vries HE. T lymphocytes impair P-glycoprotein function during neuroinflammation. J Autoimmun. 2010;34:416–425. doi: 10.1016/j.jaut.2009.10.006. [DOI] [PubMed] [Google Scholar]
  43. Kooij G, Mizee MR, van HJ, Reijerkerk A, Witte ME, Drexhage JA, Van Der Pol SM, Van Het HB, Scheffer G, Scheper R, Dijkstra CD, van der Valk P, de Vries HE. Adenosine triphosphate-binding cassette transporters mediate chemokine (C-C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. Brain. 2011;134:555–570. doi: 10.1093/brain/awq330. [DOI] [PubMed] [Google Scholar]
  44. Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A. Focal cortical dysfunction and blood–brain barrier disruption in patients with Postconcussion syndrome. J Clin Neurophysiol. 2005;22:1–9. doi: 10.1097/01.wnp.0000150973.24324.a7. [DOI] [PubMed] [Google Scholar]
  45. Kroll RA, Neuwelt EA. Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery. 1998;42:1083–1099. doi: 10.1097/00006123-199805000-00082. [DOI] [PubMed] [Google Scholar]
  46. Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210–218. doi: 10.1111/j.1750-3639.2007.00064.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Lifshitz V, Weiss R, Benromano T, Kfir E, Blumenfeld-Katzir T, Tempel-Brami C, Assaf Y, Xia W, Wyss-Coray T, Weiner HL, Frenkel D. Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model. Neurobiol Aging. 2012;33:432. doi: 10.1016/j.neurobiolaging.2011.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA. Short amyloid-beta (Abeta) immunogens reduce cerebral Aβ-eta load and learning deficits in an Alzheimer’s disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci. 2006;26:4717–4728. doi: 10.1523/JNEUROSCI.0381-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D. Seizure-promoting effect of blood–brain barrier disruption. Epilepsia. 2007a;48:732–742. doi: 10.1111/j.1528-1167.2007.00988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Marchi N, Oby E, Fernandez N, Uva L, de Curtis M, Batra A, Santaguida S, Barnes V, van Boxel A, Najm I, Janigro D. In vivo and in vitro effects of pilocarpine: relevance to epileptogenesis. Epilepsia. 2007b;48:1934–1946. doi: 10.1111/j.1528-1167.2007.01185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, Batra A, Carlton E, Najm I, Granata T, Janigro D. Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis. 2009;33:171–181. doi: 10.1016/j.nbd.2008.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Marchi N, Granata T, Freri E, Ciusani E, Ragona F, Puvenna V, Teng QS, Alexopolous A, Janigro D. Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE. 2011a;6:e18200. doi: 10.1371/journal.pone.0018200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Marchi N, Johnson A, Puvenna V, Tierney W, Ghosh C, Cucullo L, Fabene PF, Janigro D. Modulation of peripheral cytotoxic cells and ictogenesis in a model of seizures. Epilepsia. 2011b;52:1627–1634. doi: 10.1111/j.1528-1167.2011.03080.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol. 2004;3:484–492. doi: 10.1016/S1474-4422(04)00825-7. [DOI] [PubMed] [Google Scholar]
  55. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain. 1998;121:3–24. doi: 10.1093/brain/121.1.3. Pt 1. [DOI] [PubMed] [Google Scholar]
  56. Minagar A, Alexander JS. Blood–brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9:540–549. doi: 10.1191/1352458503ms965oa. [DOI] [PubMed] [Google Scholar]
  57. Monsonego A, Imitola J, Petrovic S, Zota V, Nemirovsky A, Baron R, Fisher Y, Owens T, Weiner HL. Abeta-induced meningoen-cephalitis is IFN-gamma-dependent and is associated with T cell-dependent clearance of Abeta in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2006;103:5048–5053. doi: 10.1073/pnas.0506209103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature. 2000;408:982–985. doi: 10.1038/35050116. [DOI] [PubMed] [Google Scholar]
  59. Nagababu E, Usatyuk PV, Enika D, Natarajan V, Rifkind JM. Vascular endothelial barrier dysfunction mediated by amyloid-beta proteins. J Alzheimers Dis. 2009;17:845–854. doi: 10.3233/JAD-2009-1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–452. doi: 10.1038/nm840. [DOI] [PubMed] [Google Scholar]
  61. 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 position statement. Neurobiol Aging. 2004;25:589–597. doi: 10.1016/j.neurobiolaging.2004.02.003. [DOI] [PubMed] [Google Scholar]
  62. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938–952. doi: 10.1056/NEJM200009283431307. [DOI] [PubMed] [Google Scholar]
  63. Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S, Michel BF, Boada M, Frank A, Hock C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54. doi: 10.1212/01.wnl.0000073623.84147.a8. [DOI] [PubMed] [Google Scholar]
  64. Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG, Van Nostrand WE, Cho S, Anrather J, Carlson GA, Iadecola C. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci USA. 2011;108:5063–5068. doi: 10.1073/pnas.1015413108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910. doi: 10.1056/NEJMoa044397. [DOI] [PubMed] [Google Scholar]
  66. Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH, de Graan PN. Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain. 2000;123:19–30. doi: 10.1093/brain/123.1.19. Pt 1. [DOI] [PubMed] [Google Scholar]
  67. Quadbeck G, Helmchen H. Proneness to convulsions & hematoencephalic barrier permeability. Dtsch Z Nervenheilkd. 1958;177:295–308. [PubMed] [Google Scholar]
  68. Rapoport SI, Hori M, Klatzo I. Testing of a hypothesis for osmotic opening of the blood–brain barrier. Am J Physiol. 1972;223:323–331. doi: 10.1152/ajplegacy.1972.223.2.323. [DOI] [PubMed] [Google Scholar]
  69. Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis. 2008;29:142–160. doi: 10.1016/j.nbd.2007.08.012. [DOI] [PubMed] [Google Scholar]
  70. Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol. 2009;4:462–475. doi: 10.1007/s11481-009-9166-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Rezai-Zadeh K, Gate D, Gowing G, Town T. How to get from here to there: macrophage recruitment in Alzheimer’s disease. Curr Alzheimer Res. 2011;8:156–163. doi: 10.2174/156720511795256017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009;8:205–216. doi: 10.1016/S1474-4422(09)70016-X. [DOI] [PubMed] [Google Scholar]
  73. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–177. doi: 10.1038/22124. [DOI] [PubMed] [Google Scholar]
  74. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A. Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci. 2004;24:7829–7836. doi: 10.1523/JNEUROSCI.1751-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Serafini B, Columba-Cabezas S, Di RF, Aloisi F. Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis. Am J Pathol. 2000;157:1991–2002. doi: 10.1016/S0002-9440(10)64838-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Shorvon S. The classification of status epilepticus. Epileptic Disord. 2005;7:1–3. [PubMed] [Google Scholar]
  77. Sotgiu S, Murrighile MR, Constantin G. Treatment of refractory epilepsy with natalizumab in a patient with multiple sclerosis. Case report. BMC Neurol. 2010;10:84. doi: 10.1186/1471-2377-10-84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, Lin AH, Crews L, Tremblay P, Mathews P, Mucke L, Masliah E, Wyss-Coray T. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest. 2006;116:3060–3069. doi: 10.1172/JCI27341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA. 2010;107:20816–20821. doi: 10.1073/pnas.1005888107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Tomkins O, Kaufer D, Korn A, Shelef I, Golan H, Reichenthal E, Soreq H, Friedman A. Frequent blood–brain barrier disruption in the human cerebral cortex. Cell Mol Neurobiol. 2001;21:675–691. doi: 10.1023/A:1015147920283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Udomphorn Y, Armstead WM, Vavilala MS. Cerebral blood flow and autoregulation after pediatric traumatic brain injury. Pediatr Neurol. 2008;38:225–234. doi: 10.1016/j.pediatrneurol.2007.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Uva L, Librizzi L, Marchi N, Noe F, Bongiovanni R, Vezzani A, Janigro D, de Curtis M. Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood–brain barrier permeability. Neuroscience. 2007;151:303–312. doi: 10.1016/j.neuroscience.2007.10.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Van der Goes A, Wouters D, Van Der Pol SM, Huizinga R, Ronken E, Adamson P, Greenwood J, Dijkstra CD, de Vries HE. Reactive oxygen species enhance the migration of monocytes across the blood–brain barrier in vitro. FASEB J. 2001;15:1852–1854. doi: 10.1096/fj.00-0881fje. [DOI] [PubMed] [Google Scholar]
  84. van Vliet EA, da Costa AS, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain. 2007;130:521–534. doi: 10.1093/brain/awl318. [DOI] [PubMed] [Google Scholar]
  85. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol. 2000;48:567–579. [PubMed] [Google Scholar]
  86. Weiss R, Lifshitz V, Frenkel D. TGF-beta1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis. Brain Behav Immun. 2011;25:1017–1024. doi: 10.1016/j.bbi.2010.11.012. [DOI] [PubMed] [Google Scholar]
  87. Williams K, Alvarez X, Lackner AA. Central nervous system perivascular cells are immunoregulatory cells that connect the CNS with the peripheral immune system. Glia. 2001;36:156–164. doi: 10.1002/glia.1105. [DOI] [PubMed] [Google Scholar]
  88. Wyss-Coray T, Lin C, von ED, Masliah E, Mucke L, Lacombe P. Alzheimer’s disease-like cerebrovascular pathology in transforming growth factor-beta 1 transgenic mice and functional metabolic correlates. Ann N Y Acad Sci. 2000;903:317–323. doi: 10.1111/j.1749-6632.2000.tb06382.x. [DOI] [PubMed] [Google Scholar]
  89. Zattoni M, Mura ML, Deprez F, Schwendener RA, Engelhardt B, Frei K, Fritschy JM. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci. 2011;31:4037–4050. doi: 10.1523/JNEUROSCI.6210-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Zlokovic BV. Clearing amyloid through the blood–brain barrier. J Neurochem. 2004;89:807–811. doi: 10.1111/j.1471-4159.2004.02385.x. [DOI] [PubMed] [Google Scholar]
  91. Zlokovic BV. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. doi: 10.1016/j.neuron.2008.01.003. [DOI] [PubMed] [Google Scholar]
  92. Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid beta-peptide elimination from the brain. J Neurochem. 2010;115:1077–1089. doi: 10.1111/j.1471-4159.2010.07002.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES