The Role of P-glycoprotein in Cerebral Amyloid Angiopathy; Implications for the Early Pathogenesis of Alzheimer's Disease

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.