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Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed. Correction.
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This is a very interesting manuscript that is noteworthy for its proposed mechanism linking ApoE and cerebrovascular dysfunction. The authors use a combination of genetic and pharmacological manipulations to propose a link between ApoE, cyclophilin A, and MMP9 activation. Although promising, substantially more work will be necessary to determine if the pathways/targets proposed in this manuscript are suitable for the treatment of Alzheimer's and other diseases associated with ApoE4. Below are several points worthy of further consideration:
1. The work offers yet another model by which ApoE may be mediating a general neurotoxic outcome in the brain (to be added to the many others already in the literature). As ApoE is linked to several degenerative diseases, and recovery after stroke, a general mechanism as proposed by Zlokovic and colleagues is reasonable; however, there is a wide range of previous work claiming different "general" mechanisms. My fear is that ApoE4 is pleiotropic, affecting a number of cell biological mechanisms; thus, pinpointing a specific cellular mechanism may prove elusive. Nevertheless, the authors make a concerted effort to establish a molecular mechanism driving blood-brain barrier disruption, namely, the activation of MMP9 via cyclophilin A, dismantling of the basement membrane, and downregulation of proteins regulating endothelial tight junctions.
2. Although the genetic manipulations look compelling, caution is necessary when interpreting results from pharmacological manipulations. There is no extensive pharmacokinetics/pharmacodynamics to fully assure the reader that these molecules (cyclosporine, PDTC, and SB-3CT) are specifically acting via the mechanisms proposed.
3. The model proposed by Zlokovic and colleagues does not account for the most validated observation related to Alzheimer's and ApoE4, namely, that ApoE4 increases the risk of developing amyloid plaques. Furthermore, it has been proposed that ApoE4 carriers show a reduction in Aβ efflux. This being said, it is not unreasonable to assume that ApoE is modulating multiple areas of biology as discussed above.
View all comments by Ryan WattsUniversity of Southampton School of Medicine
This paper represents a natural progression for the group that has clarified the effect of different isoforms of ApoE on the transporters that clear Aβ from the brain. Here, the group has made significant contributions in demonstrating how ApoE exerts its effect on the blood-brain barrier. The authors demonstrated first that the absence of ApoE or the presence of human ApoE4 in mice results in a leaky blood-brain barrier, associated with decreased levels of proteins expressed at the tight junctions, and decreased levels of collagen IV. Collagen IV is a glycoprotein present at the basement membranes, and it prevents the formation of Aβ fibrils. Apart from their clearance across the endothelium into the blood, solutes and Aβ are eliminated by perivascular drainage along cerebrovascular basement membranes (Hawkes et al., 2011) .
The authors then demonstrate that ApoE4 is associated with high expression of cyclophilin A (CypA) in pericytes and increased expression of matrix metalloproteinase 9 (MMP9). A series of very elegant in-vivo experiments, coupled with pharmacological and genetic manipulation, demonstrates that CypA, nuclear factor κB, and MMP9 are responsible for the breakdown in the BBB observed in the presence of ApoE4. Furthermore, the study demonstrates that the endothelium lipoprotein receptor responsible for clearance of Aβ is also present on pericytes. Isoforms of ApoE regulate the expression and function of lipoprotein receptor on pericytes. ApoE3 binds with high affinity to LRP1, whereas ApoE4 does not bind to pericyte LRP1, a result very similar to that observed in previous studies of the interactions of ApoE and LRP1 at the vascular level.
Recently, this group led by Berislav Zlokovic has clarified many of the physiological roles of pericytes in maintaining the integrity of the neurovascular unit (Winkler et al., 2011). The present study, through a series of important findings about how pericytes interact with ApoE and influence the integrity of the blood-brain barrier, is a major step in clarifying the factors behind the pathogenesis of neurodegenerative disorders. Pericytes may provide the motive force for the drainage of solutes from the extracellular spaces along vascular basement membranes. Defects in the function of pericytes may be associated with a failure of elimination of Aβ by lipoprotein receptors as well as by perivascular drainage. It is possible that targeting the activity of pericytes may become a therapeutic strategy in the treatment of neurodegenerative diseases.
References:
Hawkes CA, Härtig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011 Apr;121(4):431-43. Epub 2011 Jan 23 PubMed.
Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011 Nov;14(11):1398-405. PubMed.
View all comments by Roy WellerUT Southwestern
Fascinating paper! I am somewhat hesitant to extrapolate its relevance directly to humans; intuitively the effects seem too large for this. But mechanistically, the findings are concordant with Nishitsuji et al. This will require confirmation, of course, but the idea and the plausible mechanism definitely warrant detailed scrutiny and extension of these studies by other labs. For instance, Boucher et al. showed that loss of LRP1 in vascular smooth muscle cells results in increased activation of MMP2 and MMP9, which fits well with the results reported here by Bell et al.
What I find further tantalizing is the link it offers to cerebral amyloid angiopathy, which occurs so frequently in ApoE4 carriers. I wonder how exactly these mechanisms might be connected. On the other hand, if human ApoE4 carriers were suffering from such a large degree of blood-brain barrier (BBB) leakage, would one not expect this to manifest itself clinically in a more prominent manner? Perhaps the effect in humans is smaller than in the mouse? On the other hand, an increased incidence of glomerular nephropathy has also been reported to be associated with ApoE4, raising the possibility that the ApoE4 effect at the BBB may extend to the related mesangial cells in the kidney glomerulus.
References:
Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem. 2011 May 20;286(20):17536-42. PubMed.
Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J. LRP: role in vascular wall integrity and protection from atherosclerosis. Science. 2003 Apr 11;300(5617):329-32. PubMed.
View all comments by Joachim HerzBrown University
ApoE, Microvascular Injury, and Blood-Brain Barrier Compromise in Sporadic (Late-Onset) Alzheimer’s Disease: A Shining New Light for Therapeutic Intervention
Alzheimer’s disease (AD) is a genetically diverse spectrum of disorders that includes both familial and sporadic forms (1). The familial forms of the disease are seen in less than 10 percent of cases, and are associated with mutations on chromosomes 21 (amyloid precursor protein) (2-4), 14 (presenilin I) (5-7), and 1 (presenilin II) (8-9). Patients generally present with symptoms of cognitive impairment at an early age, have a rapidly progressive course, and exhibit severe pathologic alterations in their brains. Patients with the more common late-onset sporadic form of the disease (90 percent) are likely to be homozygous for the ApoE4 gene on chromosome 19, which codes for the high-density lipoprotein ApoE4 (10). Such patients typically exhibit symptoms of cognitive impairment later in life, have a more slowly progressive clinical course, and a variable degree of brain AD pathology. Despite the unequivocal association between ApoE4 and late-onset sporadic AD, the mechanism(s) through which ApoE4 contributes to the pathogenesis of sporadic AD remain(s) elusive.
Numerous brain imaging studies by SPECT, CT, PET, and MRI have documented a preferential decrease in cerebral blood flow to brain areas affected by AD, as well as an increase in small vessel disease in Alzheimer's patients (11-18). Microvascular disease is a common finding at autopsy in the brains of elderly patients, and significant microvascular pathology has been extensively described in AD (19-25). Various components of the fragmented vascular basement membrane are found within senile (neuritic) plaques, raising the question of whether plaque formation and microvascular pathology are somehow closely linked (26-30). Previous studies by our group and others have documented that agrin, the major heparan-sulfate proteoglycan component of the cerebral capillary basement membrane, becomes fragmented in sporadic AD, compromising microvascular structural integrity (31-34). We have also demonstrated that this structural damage is greater in AD patients with the ApoE4 genotype, and correlates with the appearance of serum-derived proteins in the brain, presumably due to a defective blood-brain barrier (35-36).
Thus far, evidence supporting a derangement in blood-brain barrier integrity in AD has been derived from clinical studies using the CSF/serum protein ratios of albumin, haptoglobin, and IgG. These studies can be roughly divided into two groups: those finding no evidence of a blood-brain barrier defect in AD (37-40), and those concluding that there is a significant compromise in blood-brain barrier integrity (41-45). Problems with experimental design may account for some of these discrepancies. Sample sizes were often limited to a very small number of patients. Most of the earlier studies failed to consider the severity of AD as a significant variable in their analyses, combining patients with both early and advanced disease into the same AD cohort. Clinical criteria for the diagnosis of AD were often vaguely defined. A trend for improvement in study design is evident in the three most recent studies, which have all concluded that blood-brain barrier integrity is clearly compromised in AD patients (43-45).
This landmark paper by Bell et al. demonstrates, through an elegant series of experiments in genetically altered mice, that expression of human ApoE4 and lack of murine ApoE leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes (46). This then leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. The potential therapeutic relevance of these animal model investigations is strongly supported by prior studies using postmortem brain tissue from Alzheimer's patients, generously provided by their families.
Aging and brain trauma in human patients may both impair the BBB (perhaps synergistically) through the exact mechanisms described in this exciting report, setting into motion a cascade of pathologic processes that destabilize brain fluid homeostasis and lead to cognitive decline. Information gained from these experiments may lead to earlier identification and therapeutic intervention. Pharmacologic and epigenetic manipulations, related to preserving the neurovascular unit and BBB, clearly represent an exciting new approach for reducing the onset and progression of dementia in sporadic AD patients.
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Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed. Correction.
View all comments by Edward G. StopaNational Institute on Aging
This paper by Bell and colleagues reports exciting findings that suggest novel mechanisms underlying the role of ApoE genotype in neurodegeneration. They implicate ApoE4 in the breakdown of blood-brain barrier (BBB) integrity, an effect that is mediated by cyclophilin A. The compromised BBB appears to facilitate accumulation of blood-derived neurotoxic proteins, including fibrin, hemosiderin, and thrombin in ApoE4 mice. The authors delineate the temporal course of these changes and provide evidence that vascular dysfunction as reflected in disruption of the BBB precedes neuronal dysfunction in ApoE-negative and ApoE4 mice. These findings provide novel insights into the role of ApoE genotype in provoking neuronal dysfunction/synaptic failure. While extrapolating findings from animal models to humans is fraught with many a broken promise, it is tempting to speculate on the potential implications for Alzheimer’s disease.
These results may offer a mechanistic explanation for the observations that cognitively normal individuals who are ApoE4 carriers show evidence for early neuronal dysfunction/synaptic failure (1,2). More recently, ApoE4 carriers were found to be especially susceptible to neurotoxic adverse effects observed in patients in a clinical trial of a humanized monoclonal antibody against amyloid-β. The spectrum of imaging abnormalities in these individuals includes vasogenic edema, sulcal effusions, microhemorrhages, and hemosiderin deposits (3). Whether or not the findings reported by Bell and colleagues will eventually lead to the identification of therapeutic targets against neuronal dysfunction or neurotoxicity in at-risk individuals remains to be seen.
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