The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease

Abstract

It has been shown in vitro that beta-amyloid (Abeta) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that Abeta 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 Abeta in normal aging and particularly in Alzheimer's disease (AD). As we were interested in the early pathogenesis of Abeta 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 Abeta were never colocalized, i.e., vessels with high P-gp expression showed no Abeta deposition in their walls, and vice versa. Abeta deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of Abeta. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase Abeta 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 Abeta 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 Abeta clearance could lead to the accumulation and earlier deposition of Abeta, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.

Fig. (1)

P-gp expression decreases significantly with age (cases without CAA). * P<0.05 (+/− standard error of mean)

Fig. (2)

P-gp expression and Aβ40-CAA frequency in hippocampus, cortex and leptomeninges. * P<0.05

Fig. (3)

P-gp expression and Aβ42-CAA frequency in hippocampus, cortex and leptomeninges. * P<0.05

Fig. (4)

Fig. (4a and b). Double immunofluorescence of P-gp (green) and amyloid (red) with laser scanning microscopy. P-gp and CAA are not colocalized.