ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage

New evidence appearing in today’s Nature implicates the ApoE4 allele, the primary genetic risk factor for late-onset Alzheimer’s disease, as a prime culprit in damaging brain blood vessels. Although scientists suspected that ApoE4 worked some mischief at the blood-brain barrier (BBB), the mechanism was unknown. Now, researchers led by Berislav Zlokovic, previously at the University of Rochester, New York, and now at the University of Southern California, Los Angeles, describe a detailed inflammatory pathway through which human ApoE4 triggers BBB breakdown in transgenic mice. This breakdown causes toxic serum proteins to accumulate in the brain and provokes neuronal degeneration, the authors report. Notably, this occurs in the absence of any Aβ. Zlokovic and colleagues were able to restore the BBB and improve the neuronal health of the mice through genetic and pharmacological manipulations of the pathway, suggesting this mechanism could be a therapeutic target in ApoE4 carriers, who make up the majority of sporadic AD cases. However, it remains to be seen whether the results will translate to humans, and whether the pathway will be amenable to drug development. First author Robert Bell at the University of Rochester previously presented some of this research at the 2010 Society for Neuroscience annual conference in San Diego, California (see ARF related news story).

Other scientists contacted by Alzforum expressed enthusiasm for the findings. “The paper is a tour de force in pinning down a role for ApoE in vascular protection,” said Cheryl Wellington at the University of British Columbia, Vancouver, Canada. “This is an important paper, because it describes a very early event in AD pathogenesis that could precede a lot of other downstream things.”

Researchers have struggled to nail down precisely how ApoE4 inflates AD risk because the protein acts on so many cellular processes (see ARF related news story). In particular, ApoE4 promotes amyloid-β deposition, giving it a direct role in AD pathology (see ARF related news story). How does Aβ, which is present in human AD, relate to ApoE’s actions at the BBB? Zlokovic told Alzforum he favors a two-hit hypothesis. He believes ApoE4 first damages the cerebrovasculature, kicking off a cascade of brain damage, then, as a second hit, amplifies Aβ deposition (see Zlokovic, 2011). Other scientists agreed that the BBB mechanism is probably an important contributor to brain damage, but is unlikely to explain all of the AD risk conferred by ApoE4, and may act in tandem with Aβ-dependent pathways. “Cerebrovascular degeneration in concert with Aβ [deposition] could have a synergistic effect on cognition,” suggested Donna Wilcock at the University of Kentucky, Lexington.

To study the vascular role of ApoE, Bell and colleagues used mice in which the endogenous mouse protein was replaced with human ApoE2, 3, or 4, as well as ApoE knockout animals. In two-week-old mice with ApoE4 or no ApoE, cerebral blood vessels leaked profusely, capillary length declined, and cerebral blood flow dropped. These changes grew worse with age. Intriguingly, levels of the proinflammatory cytokine, cyclophilin A (CypA), which has been shown to damage blood vessels (see Satoh et al., 2009; Jin et al., 2004), jumped fivefold in these animals compared to ApoE2 and ApoE3 mice. The CypA explosion occurred in pericytes, a type of cell that wraps around small blood vessels. When the authors crossed ApoE4 and knockout animals with mice lacking CypA, the BBB remained intact. Feeding the mice cyclosporine A, a CypA inhibitor, also tightened up the BBB.

The authors then dissected how ApoE4 induces CypA. They found that ApoE, which is predominantly made by astrocytes in the brain, binds to low-density lipoprotein receptor-related protein 1 (LRP1) on pericytes. The ApoE4 allele, however, fails to bind the receptor, as shown by proximity ligation assay, a highly sensitive type of immunoassay (see Fredriksson et al., 2002; Söderberg et al., 2006). In ApoE4 or ApoE knockout mice, CypA synthesis goes wild. The cytokine then activates pericyte nuclear factor κB (NF-κB), which translocates to the nucleus and pumps up production of matrix metalloproteinase 9 (MMP9). This proteinase chews up capillary basement membrane and tight junction proteins, effectively punching holes in the blood-brain barrier. Interfering with any step in this pathway, by pharmacological inhibitors, short interfering RNA, or genetic deletion, restored BBB function, the authors report.

Furthermore, the brains of ApoE4 and knockout mice accumulated serum proteins such as fibrin, thrombin, and hemosiderin, which can poison neurons (see Grammas, 2011; Paul et al., 2007). Bell and colleagues showed that, by four months of age, ApoE4 mice had less neuronal activity and were losing neurites and synaptic proteins. Inhibiting the CypA-MMP9 pathway partially reversed this neurodegeneration, improving neuron structure and function. In future work, Zlokovic said he will test behavior and information processing in these mice to see if the neuronal losses correlate with cognitive problems.

One big question is whether these findings relate to humans. Zlokovic plans to examine cerebrospinal fluid from AD patients to see if the main markers of this inflammatory pathway, CypA and MMP9, are elevated in people with the ApoE4 allele. In collaboration with colleagues at the University of Southern California, he is also developing methods using MRI to look at BBB health in AD patients. The task is challenging, because small flaws in capillaries typically do not show up on MRIs, he noted.

Neurodegenerative conditions such as AD frequently go hand-in-hand with BBB disruption (see, e.g., Farrall and Wardlaw, 2009; Dickstein et al., 2010), and vascular flaws appear to be more pronounced in people carrying the ApoE4 allele (see Salloway et al., 2002). People with the ApoE4 allele are known to have higher levels of cerebral amyloid angiopathy (CAA) and be more susceptible to microhemorrhages compared to non-carriers, which has caused problems for this group in immunotherapy trials, Wilcock pointed out (see, e.g., ARF related news story). Wilcock recently showed that giving immunotherapy to mice activates the MMP9 pathway, which may help explain some of the vascular damage seen in trials (see Wilcock et al., 2011). Zlokovic’s study now highlights why ApoE4 carriers may be particularly susceptible to this mechanism. It also holds out hope that “Maybe we now have a targetable pathway in ApoE4s,” Wilcock said. “I think all of this is going to start pointing us toward a more personalized therapeutic approach, as opposed to a one-size-fits-all.”

The ApoE4 allele is also a risk factor for other neurodegenerative conditions, such as Parkinson’s and multiple sclerosis (see ARF related news story). Having an E4 allele worsens a person’s outcome after ischemic or traumatic brain injury, noted Yadong Huang at the Gladstone Institute for Neurological Disease, San Francisco, California (see Mayeux et al., 1995 and ARF related news story). Huang believes the new findings have relevance for these conditions, too. “Whenever you have trauma or brain injury, cerebrovascular integrity is critical,” he said.

While the new data suggest that inhibiting the CypA-MMP9 pathway could reverse vascular problems and perhaps prevent brain damage in ApoE4 carriers, the route from an academic result to a usable drug is a long and arduous one, cautioned Ryan Watts at Genentech, South San Francisco, California. Because most chemical inhibitors are “dirty,” hitting many targets, researchers need to perform careful pharmacodynamic and pharmacokinetic studies over a range of doses to be sure a drug is selectively inhibiting the desired target, he said. Also, molecules such as MMP9 and CypA act on many pathways and have beneficial effects as well, which means that inhibiting them long term could have undesirable side effects. “Although promising, substantially more work will be necessary to determine if these pathways/targets proposed in this manuscript are suitable for the treatment of Alzheimer's and other diseases associated with ApoE4,” Watts wrote (see full comment below).—Madolyn Bowman Rogers

Comments

  1. 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 Watts
    • User Profile Image Roy Weller
      University of Southampton School of Medicine
    • Posted:

    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 Weller

  3. 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 Herz

  4. 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.

    References:

    Davies P. The genetics of Alzheimer's disease: a review and a discussion of the implications. Neurobiol Aging. 1986 Nov-Dec;7(6):459-66. PubMed.

    Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880-4. PubMed.

    Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. PubMed.

    Robakis NK, Wisniewski HM, Jenkins EC, Devine-Gage EA, Houck GE, Yao XL, Ramakrishna N, Wolfe G, Silverman WP, Brown WT. Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome. Lancet. 1987 Feb 14;1(8529):384-5. PubMed.

    Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

    Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363-71. PubMed.

    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.

    Cruts M, Hendriks L, Van Broeckhoven C. The presenilin genes: a new gene family involved in Alzheimer disease pathology. Hum Mol Genet. 1996;5 Spec No:1449-55. PubMed.

    Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Merriam DE, Hollister RD, Hallmark OG, Mancini R, Felsenstein KM, Hyman BT, Tanzi RE, Wasco W. Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat Med. 1996 Feb;2(2):224-9. PubMed.

    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.

    Fujii K, Sadoshima S, Okada Y, Yao H, Kuwabara Y, Ichiya Y, Fujishima M. Cerebral blood flow and metabolism in normotensive and hypertensive patients with transient neurologic deficits. Stroke. 1990 Feb;21(2):283-90. PubMed.

    Nakane H, Ibayashi S, Fujii K, Irie K, Sadoshima S, Fujishima M. Cerebral blood flow and metabolism in hypertensive patients with cerebral infarction. Angiology. 1995 Sep;46(9):801-10. PubMed.

    Nobili F, Rodriguez G, Marenco S, De Carli F, Gambaro M, Castello C, Pontremoli R, Rosadini G. Regional cerebral blood flow in chronic hypertension. A correlative study. Stroke. 1993 Aug;24(8):1148-53. PubMed.

    Eberling JL, Jagust WJ, Reed BR, Baker MG. Reduced temporal lobe blood flow in Alzheimer's disease. Neurobiol Aging. 1992 Jul-Aug;13(4):483-91. PubMed.

    Dekosky ST, Shih WJ, Schmitt FA, Coupal J, Kirkpatrick C. Assessing utility of single photon emission computed tomography (SPECT) scan in Alzheimer disease: correlation with cognitive severity. Alzheimer Dis Assoc Disord. 1990;4(1):14-23. PubMed.

    Scheltens P, Barkhof F, Valk J, Algra PR, van der Hoop RG, Nauta J, Wolters EC. White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer's disease. Evidence for heterogeneity. Brain. 1992 Jun;115 ( Pt 3):735-48. PubMed.

    Doddy RS, Massman PJ, Mawad M, Nance M. Cognitive consequences of subcortical magnetic resonance imaging changes in Alzheimer's disease: comparison to small vessel ischemic vascular dementia. Neuropsychiatry Neuropsychol Behav Neurol. 1998 Oct;11(4):191-9. PubMed.

    Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA, Nilsson L, Persson G, Odén A, Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996 Apr 27;347(9009):1141-5. PubMed.

    Buée L, Hof PR, Delacourte A. Brain microvascular changes in Alzheimer's disease and other dementias. Ann N Y Acad Sci. 1997 Sep 26;826:7-24. PubMed.

    Perry G, Smith MA, McCann CE, Siedlak SL, Jones PK, Friedland RP. Cerebrovascular muscle atrophy is a feature of Alzheimer's disease. Brain Res. 1998 Apr 27;791(1-2):63-6. PubMed.

    Mancardi GL, Perdelli F, Rivano C, Leonardi A, Bugiani O. Thickening of the basement membrane of cortical capillaries in Alzheimer's disease. Acta Neuropathol. 1980;49(1):79-83. PubMed.

    Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996 Mar 14;380(6570):168-71. PubMed.

    Claudio L. Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's disease patients. Acta Neuropathol. 1996;91(1):6-14. PubMed.

    Mancardi GL, Tabaton M, Liwnicz BH. Endothelial mitochondrial content of cerebral cortical capillaries in Alzheimer's disease. An ultrastructural quantitative study. Eur Neurol. 1985;24(1):49-52. PubMed.

    Perlmutter LS, Myers MA, Barrón E. Vascular basement membrane components and the lesions of Alzheimer's disease: light and electron microscopic analyses. Microsc Res Tech. 1994 Jun 15;28(3):204-15. PubMed.

    Perry G, Siedlak SL, Richey P, Kawai M, Cras P, Kalaria RN, Galloway PG, Scardina JM, Cordell B, Greenberg BD. Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer's disease. J Neurosci. 1991 Nov;11(11):3679-83. PubMed.

    Snow AD, Mar H, Nochlin D, Kimata K, Kato M, Suzuki S, Hassell J, Wight TN. The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. Am J Pathol. 1988 Dec;133(3):456-63. PubMed.

    Roll FJ, Madri JA, Albert J, Furthmayr H. Codistribution of collagen types IV and AB2 in basement membranes and mesangium of the kidney. an immunoferritin study of ultrathin frozen sections. J Cell Biol. 1980 Jun;85(3):597-616. PubMed.

    Murtomäki S, Risteli J, Risteli L, Koivisto UM, Johansson S, Liesi P. Laminin and its neurite outgrowth-promoting domain in the brain in Alzheimer's disease and Down's syndrome patients. J Neurosci Res. 1992 Jun;32(2):261-73. PubMed.

    McGeer PL, Zhu SG, Dedhar S. Immunostaining of human brain capillaries by antibodies to very late antigens. J Neuroimmunol. 1990 Mar;26(3):213-8. PubMed.

    Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG. Agrin and microvascular damage in Alzheimer's disease. Neurobiol Aging. 2000 Mar-Apr;21(2):349-55. PubMed.

    Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG. Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6468-72. PubMed.

    Cotman SL, Halfter W, Cole GJ. Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain. Mol Cell Neurosci. 2000 Feb;15(2):183-98. PubMed.

    Verbeek MM, Otte-Höller I, van den Born J, van den Heuvel LP, David G, Wesseling P, de Waal RM. Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease brain. Am J Pathol. 1999 Dec;155(6):2115-25. PubMed.

    Salloway S, Gur T, Berzin T, Tavares R, Zipser B, Correia S, Hovanesian V, Fallon J, Kuo-Leblanc V, Glass D, Hulette C, Rosenberg C, Vitek M, Stopa E. Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease. J Neurol Sci. 2002 Nov 15;203-204:183-7. PubMed.

    Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging. 2007 Jul;28(7):977-86. Epub 2006 Jun 16 PubMed.

    Leonardi A, Gandolfo C, Caponnetto C, Arata L, Vecchia R. The integrity of the blood-brain barrier in Alzheimer's type and multi-infarct dementia evaluated by the study of albumin and IgG in serum and cerebrospinal fluid. J Neurol Sci. 1985 Feb;67(2):253-61. PubMed.

    Kay AD, May C, Papadopoulos NM, Costello R, Atack JR, Luxenberg JS, Cutler NR, Rapoport SI. CSF and serum concentrations of albumin and IgG in Alzheimer's disease. Neurobiol Aging. 1987 Jan-Feb;8(1):21-5. PubMed.

    Frölich L, Kornhuber J, Ihl R, Fritze J, Maurer K, Riederer P. Integrity of the blood-CSF barrier in dementia of Alzheimer type: CSF/serum ratios of albumin and IgG. Eur Arch Psychiatry Clin Neurosci. 1991;240(6):363-6. PubMed.

    Mecocci P, Parnetti L, Reboldi GP, Santucci C, Gaiti A, Ferri C, Gernini I, Romagnoli M, Cadini D, Senin U. Blood-brain-barrier in a geriatric population: barrier function in degenerative and vascular dementias. Acta Neurol Scand. 1991 Sep;84(3):210-3. PubMed.

    Alafuzoff I, Adolfsson R, Bucht G, Winblad B. Albumin and immunoglobulin in plasma and cerebrospinal fluid, and blood-cerebrospinal fluid barrier function in patients with dementia of Alzheimer type and multi-infarct dementia. J Neurol Sci. 1983 Aug-Sep;60(3):465-72. PubMed.

    Blennow K, Wallin A, Fredman P, Karlsson I, Gottfries CG, Svennerholm L. Blood-brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors. Acta Neurol Scand. 1990 Apr;81(4):323-6. PubMed.

    Hampel H, Müller-Spahn F, Berger C, Haberl A, Ackenheil M, Hock C. Evidence of blood-cerebrospinal fluid-barrier impairment in a subgroup of patients with dementia of the Alzheimer type and major depression: a possible indicator for immunoactivation. Dementia. 1995 Nov-Dec;6(6):348-54. PubMed.

    Skoog I, Wallin A, Fredman P, Hesse C, Aevarsson O, Karlsson I, Gottfries CG, Blennow K. A population study on blood-brain barrier function in 85-year-olds: relation to Alzheimer's disease and vascular dementia. Neurology. 1998 Apr;50(4):966-71. PubMed.

    Wada H. Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio. Intern Med. 1998 Jun;37(6):509-13. PubMed.

    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. Stopa

  5. 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.

    References:

    Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM. APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol. 2010 Jan;67(1):93-8. PubMed.

    Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9. PubMed.

    Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012 Mar;11(3):241-9. PubMed.

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References

News Citations

  1. San Diego: The Curious Case of ApoE, Cholesterol, and Cognition
  2. Keystone: Symposium Emphasizes Key Aspects of ApoE Biology
  3. Miami: Age and Amyloid—What Has ApoE Got to Do With It?
  4. Paper Alert-cum-SfN: Bapineuzumab Published, More AN1792 Presented
  5. Keystone: Does ApoE Fragmentation Drive Pathology?
  6. Stress and Trauma: Aβ’s Mysterious Role in Severe Brain Injury

Paper Citations

  1. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723-38. PubMed.
  3. Jin ZG, Lungu AO, Xie L, Wang M, Wong C, Berk BC. Cyclophilin A is a proinflammatory cytokine that activates endothelial cells. Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1186-91. PubMed.
  4. Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gústafsdóttir SM, Ostman A, Landegren U. Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol. 2002 May;20(5):473-7. PubMed.
  5. Söderberg O, Gullberg M, Jarvius M, Ridderstråle K, Leuchowius KJ, Jarvius J, Wester K, Hydbring P, Bahram F, Larsson LG, Landegren U. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006 Dec;3(12):995-1000. PubMed.
  6. Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease. J Neuroinflammation. 2011;8:26. PubMed.
  7. Paul J, Strickland S, Melchor JP. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J Exp Med. 2007 Aug 6;204(8):1999-2008. PubMed.
  8. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol Aging. 2009 Mar;30(3):337-52. PubMed.
  9. Dickstein DL, Walsh J, Brautigam H, Stockton SD, Gandy S, Hof PR. Role of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J Med. 2010 Jan-Feb;77(1):82-102. PubMed.
  10. Salloway S, Gur T, Berzin T, Tavares R, Zipser B, Correia S, Hovanesian V, Fallon J, Kuo-Leblanc V, Glass D, Hulette C, Rosenberg C, Vitek M, Stopa E. Effect of APOE genotype on microvascular basement membrane in Alzheimer's disease. J Neurol Sci. 2002 Nov 15;203-204:183-7. PubMed.
  11. Wilcock DM, Morgan D, Gordon MN, Taylor TL, Ridnour LA, Wink DA, Colton CA. Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence. J Neuroinflammation. 2011;8:115. PubMed.
  12. Mayeux R, Ottman R, Maestre G, Ngai C, Tang MX, Ginsberg H, Chun M, Tycko B, Shelanski M. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology. 1995 Mar;45(3 Pt 1):555-7. PubMed.

External Citations

  1. ApoE4 allele

Further Reading

Primary Papers

  1. 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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