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Regional differences of the effects of aging on perivascular drainage of amyloid-B from the mouse brain

Regional differences of the effects of aging on perivascular drainage of amyloid-B from the mouse brain
Regional differences of the effects of aging on perivascular drainage of amyloid-B from the mouse brain
Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-? (A?) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of A? contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble A? into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of A? in the brain in AD and may facilitate development of improved therapeutic strategies to remove A? from the brain in AD.

aging, alzheimer's disease, basement membranes, cerebral amyloid angiopathy, cerebral vasculature
1474-9718
224-236
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Gatherer, M.
b0aae216-21c4-4737-b042-865a65658f06
Sharp, M.
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Dorr, A.
12479cb3-5a4c-42f1-be1f-32822aa77f09
Yuen, H.M.
b1df4c57-0c2a-44ac-ab40-22b88e8effe8
Kalaria, R.
32b27b6a-8b1a-455e-b2e8-1b6800a7711a
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Carare, R.O.
0478c197-b0c1-4206-acae-54e88c8f21fa
Hawkes, C.A.
88f4a99a-625c-4c6e-a295-09dd67f8afe8
Gatherer, M.
b0aae216-21c4-4737-b042-865a65658f06
Sharp, M.
ec57c53a-a10a-4b8a-94fe-03eca85ab7c3
Dorr, A.
12479cb3-5a4c-42f1-be1f-32822aa77f09
Yuen, H.M.
b1df4c57-0c2a-44ac-ab40-22b88e8effe8
Kalaria, R.
32b27b6a-8b1a-455e-b2e8-1b6800a7711a
Weller, R.O.
4a501831-e38a-4d39-a125-d7141d6c667b
Carare, R.O.
0478c197-b0c1-4206-acae-54e88c8f21fa

Hawkes, C.A., Gatherer, M., Sharp, M., Dorr, A., Yuen, H.M., Kalaria, R., Weller, R.O. and Carare, R.O. (2013) Regional differences of the effects of aging on perivascular drainage of amyloid-B from the mouse brain. Aging Cell, 12 (2), 224-236. (doi:10.1111/acel.12045). (PMID:23413811)

Record type: Article

Abstract

Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-? (A?) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of A? contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble A? into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of A? in the brain in AD and may facilitate development of improved therapeutic strategies to remove A? from the brain in AD.

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e-pub ahead of print date: February 2013
Published date: 18 February 2013
Keywords: aging, alzheimer's disease, basement membranes, cerebral amyloid angiopathy, cerebral vasculature
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 353190
URI: http://eprints.soton.ac.uk/id/eprint/353190
ISSN: 1474-9718
PURE UUID: f1655fa7-a87e-407f-9fe4-b95ee2aba56f
ORCID for M. Sharp: ORCID iD orcid.org/0000-0002-6623-5078

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Date deposited: 03 Jun 2013 12:25
Last modified: 18 Feb 2021 17:14

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Contributors

Author: C.A. Hawkes
Author: M. Gatherer
Author: M. Sharp ORCID iD
Author: A. Dorr
Author: H.M. Yuen
Author: R. Kalaria
Author: R.O. Weller
Author: R.O. Carare

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