Journal
CURRENT ALZHEIMER RESEARCH
Volume 1, Issue 2, Pages 121-125Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205043332225
Keywords
Alzheimer; apolipoprotein E; P-glycoprotein; cerebral amyloid angiopathy; risk factors; senile plaques; vascular amyloid; MDR1; degeneration
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Funding
- NCRR NIH HHS [P51 RR000165-440234, P51 RR000165-486002, P51 RR000165] Funding Source: Medline
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It has been shown in vitro that beta-amyloid (A beta) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that A beta immunoreactivity is significantly elevated in brain tissue of individuals with low expression of P-gp in vascular endothelial cells. These findings led us to hypothesize that P-gp might be involved in the clearance of A beta in normal aging and particularly in Alzheimer's disease (AD). As we were interested in the early pathogenesis of A beta deposition, we studied the correlation between cerebral amyloid angiopathy (CAA) and P-gp expression in brain tissue samples from 243 non-demented elderly cases (aged 50 to 91 years). We found that endothelial P-gp and vascular A beta were never colocalized, i.e., vessels with high P-gp expression showed no A beta deposition in their walls, and vice versa. A beta deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of A beta. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase A beta clearance from the brain. Capillaries were usually affected only at later stages of CAA, at which point P-gp was lost even in these vessels. We hypothesize that A beta clearance may be altered in individuals with diminished P-gp expression due, e. g., to genetic or environmental effects (such as drug administration). The impairment of A beta clearance could lead to the accumulation and earlier deposition of A beta, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.
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