Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy

Greenberg, Steven M.; Vonsattel, Jean‐Paul; Segal, Alan Z.; Chiu, Rosaleen I.; Clatworthy, Anne E.; Liao, Andrew; Hyman, B. T.; Rebeck, G. William

doi:10.1212/wnl.50.4.961

Cited by 234 publications

(171 citation statements)

References 17 publications

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“…5 Ab , being primarily vasculotropic, is found in the brain vasculature of CAA patients and in experimental models of the disease, whereas Ab 1-42 , endowed with distinct trophism for neurons, predominates in the brain parenchyma of AD patients. [6][7][8][9] Brain vascular degeneration, typical of both sporadic and genetic variants of CAA, is characterized by perivascular deposition of Ab in cortical and leptomeningeal vessels. 9 The hallmark pathological lesion of these diseases is the pervasive dysfunction of brain capillary endothelium.…”

Section: Introductionmentioning

confidence: 99%

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

et al. 2006

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Recent evidences suggest that Ab peptides modulate endothelial cell (EC) functions. At low concentrations, Ab 1-40 enhances the pro-angiogenic activity of FGF-2, whereas deposition of excess Ab causes EC dysfunction and cerebral amyloid angiopathy (CAA). We investigated whether FGF-2 attenuates EC dysfunction caused by pathological Ab levels. We studied Ab 1-40 on EC survival, as well as on signals responsible of their angiogenic phenotype. At 5-50 lM Ab 1-40 reduced EC population, caused apoptosis, downregulated FGF-2 production, inhibited FGF-2 binding to heparin, and FGFR1 phosphorylation. Toxic effects were owing to lack of FGF-2 stimulation, as EC overexpressing FGF-2 displayed extraordinary resistance to Ab 1-40 injuries. The FGF-2 mechanism responsible for reversing damages, involves the downstream enhancement of Akt, a pathway independent of eNOS activation.In conclusion, we demonstrate that FGF-2 protects EC from the effects of excess Ab 1-40 , suggesting that it may attenuate the consequences of Ab deposition in pathologies as CAA.

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Section: Introductionmentioning

confidence: 99%

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

et al. 2006

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“…Studies comparing normal controls against those with pathology positive CAA reveal that both APOE ε2 and ε4 are present in two-thirds of patients with CAA compared to one-fourth of those without. Individuals who have both alleles have an earlier onset of disease and an increased risk of recurrence [16,21,23]. Both APOE ε2 and ε4 are independent risk factors for lobar ICH, however, in the same large-scale genetic association study, APOE ε4 was also found to be associated with deep ICH [24].…”

Section: Cerebral Amyloid Angiopathymentioning

confidence: 97%

“…The presence of the ε4 and ε2 genes may result in increased vulnerability of amyloid laden blood vessels. The ε4 allele has been demonstrated to increase the amyloid deposition [26], whereas the ε2 allele can induce necrosis of blood vessels with amyloid deposits [23].…”

Section: Cerebral Amyloid Angiopathymentioning

confidence: 99%

Treatment Targets in Intracerebral Hemorrhage

Sangha

Gonzales

2011

Neurotherapeutics

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Intracerebral hemorrhage (ICH) imparts a higher mortality and morbidity than ischemic stroke. The therapeutic interventions that are currently available focus mainly on supportive care and secondary prevention. There is a paucity of evidence to support any one acute intervention that improves functional outcome. This chapter highlights current treatment targets for ICH based on the pathophysiology of the disease.

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“…However, the APOE e2 allele has been associated with vasculopathic changes including vessel dilation, fibrinoid necrosis, microaneurysms, and double barreling. 64 …”

Section: Apolipoprotein Ementioning

confidence: 99%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy

Abstract: These data suggest that APOE epsilon2 and epsilon4 might promote CAA-related hemorrhage through separate mechanisms: epsilon4 by enhancing amyloid deposition and epsilon2 by causing amyloid-laden vessels to undergo the vasculopathic changes that lead to rupture.

Cited by 234 publications

References 17 publications

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

Treatment Targets in Intracerebral Hemorrhage

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

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