Abstract
We measured age-dependent effects of human ApoE4 on cerebral blood flow (CBF) using
ApoE4 transgenic mice compared to age-matched wild-type (WT) mice by use of [14C] iodoantipyrene autoradiography. ApoE4 associated factors reduce CBF gradually to
create brain hypoperfusion when compared to WT, and the differences in CBF are greatest
as animals age from 6-weeks to 12-months. Transmission electron microscopy with colloidal
gold immunocytochemistry showed structural damage in young and aged microvessel endothelium
of ApoE4 animals extended to the cytoplasm of perivascular cells, perivascular nerve
terminals and hippocampal neurons and glial cells. These abnormalities coexist with
mitochondrial structural alteration and mitochondrial DNA overproliferation and/or
deletion in all brain cellular compartments. Spatial memory and temporal memory tests
showed a trend in improving cognitive function in ApoE4 mice fed selective mitochondrial
antioxidants acetyl-l-carnitine and R-α-lipoic acid. Our findings indicate that ApoE4
genotype-induced mitochondrial changes and associated structural damage may explain
age-dependent pathology seen in AD, indicating potential for novel treatment strategies
in the near future.
Keywords
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Published online: April 02, 2009
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© 2009 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
