The Role of P-glycoprotein in Cerebral Amyloid Angiopathy; Implications for the Early Pathogenesis of Alzheimers Disease
Silke Vogelgesang, Rolf W. Warzok, Ingolf Cascorbi, Christiane Kunert-Keil, Eike Schroeder, Heyo K. Kroemer, Werner Siegmund, Lary C. Walker and Jens Pahnke
Affiliation: University Hospital Zurich,Department of Pathology, F Patho 21, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
It has been shown in vitro that β-amyloid (Aβ) is transported by P-glycoprotein (P-gp). Previously, we demonstrated that Aβ 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 Aβ in normal aging and particularly in Alzheimers disease (AD). As we were interested in the early pathogenesis of Aβ 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 Aβ were never colocalized, i.e., vessels with high P-gp expression showed no Aβ deposition in their walls, and vice versa. Aβ deposition occurred first in arterioles where P-gp expression was primarily low, and disappeared completely with the accumulation of Aβ. At this early stage, P-gp was upregulated in capillaries, suggesting a compensatory mechanism to increase Aβ 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 Aβ 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 Aβ clearance could lead to the accumulation and earlier deposition of Aβ, both in the walls of blood vessels and in the brain parenchyma, thus elevating the risk of CAA and AD.
Keywords: alzheimer, apolipoprotein e, p-glycoprotein, cerebral amyloid angiopathy, risk factors, senile plaques, vascular amyloid, mdri, degeneration
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