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Disruption of arterial perivascular drainage of amyloid-? from the brains of mice expressing the human APOE ?4 allele

Disruption of arterial perivascular drainage of amyloid-? from the brains of mice expressing the human APOE ?4 allele
Disruption of arterial perivascular drainage of amyloid-? from the brains of mice expressing the human APOE ?4 allele
Failure of elimination of amyloid-? (A?) 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) ?4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ?4 allele is associated with disruption of perivascular drainage of A? 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 A?40. A?40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of A? 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 A? 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 A? from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.
1932-6203
890-901
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Sullivan, P.M.
e3fe69ee-5933-4206-b3f5-2a8a498f76ca
Hands, S.
55156699-63e7-40d5-a9bc-639c57dd4c82
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Nicoll, J.A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Sullivan, P.M.
e3fe69ee-5933-4206-b3f5-2a8a498f76ca
Hands, S.
55156699-63e7-40d5-a9bc-639c57dd4c82
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Nicoll, J.A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Carare, Roxana O.
0478c197-b0c1-4206-acae-54e88c8f21fa

Hawkes, C.A., Sullivan, P.M., Hands, S., Weller, R.O., Nicoll, J.A.R. and Carare, Roxana O. (2012) Disruption of arterial perivascular drainage of amyloid-? from the brains of mice expressing the human APOE ?4 allele. PLoS ONE, 9 (8), 890-901. (doi:10.1371/journal.pone.0041636).

Record type: Article

Abstract

Failure of elimination of amyloid-? (A?) 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) ?4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ?4 allele is associated with disruption of perivascular drainage of A? 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 A?40. A?40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of A? 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 A? 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 A? from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.

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Published date: July 2012
Organisations: Faculty of Medicine

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Local EPrints ID: 353199
URI: http://eprints.soton.ac.uk/id/eprint/353199
ISSN: 1932-6203
PURE UUID: 7543a506-f904-4906-9afb-4740c3c36cc4
ORCID for J.A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 03 Jun 2013 11:44
Last modified: 17 Dec 2019 01:50

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Contributors

Author: C.A. Hawkes
Author: P.M. Sullivan
Author: S. Hands
Author: R.O. Weller
Author: J.A.R. Nicoll ORCID iD

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