Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.

Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the d...

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Autores principales:	Cheryl A Hawkes, Patrick M Sullivan, Sarah Hands, Roy O Weller, James A R Nicoll, Roxana O Carare
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5d95f3ca471547a880508f220d1f007f
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spelling	oai:doaj.org-article:5d95f3ca471547a880508f220d1f007f2021-11-18T07:11:05ZDisruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.1932-620310.1371/journal.pone.0041636https://doaj.org/article/5d95f3ca471547a880508f220d1f007f2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22848551/?tool=EBIhttps://doaj.org/toc/1932-6203Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.Cheryl A HawkesPatrick M SullivanSarah HandsRoy O WellerJames A R NicollRoxana O CararePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41636 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cheryl A Hawkes Patrick M Sullivan Sarah Hands Roy O Weller James A R Nicoll Roxana O Carare Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
description	Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.
format	article
author	Cheryl A Hawkes Patrick M Sullivan Sarah Hands Roy O Weller James A R Nicoll Roxana O Carare
author_facet	Cheryl A Hawkes Patrick M Sullivan Sarah Hands Roy O Weller James A R Nicoll Roxana O Carare
author_sort	Cheryl A Hawkes
title	Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
title_short	Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
title_full	Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
title_fullStr	Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
title_full_unstemmed	Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.
title_sort	disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human apoe ε4 allele.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/5d95f3ca471547a880508f220d1f007f
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Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.

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