The Role of P-glycoprotein in Cerebral Amyloid Angiopathy; Implications for the Early Pathogenesis of Alzheimers 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.

Astrocytic transporters in Alzheimer's disease

“…This evidence suggests that accumulation of the toxic form of Aβ can lead to downregulation of the P-glycoprotein 1 transporter. This correlates with human studies that reported elevated levels of Aβ and decreases in P-glycoprotein 1 levels (233,234). The relative contributions to Aβ clearance from capillaries and astrocytes remains to be fully understood.…”

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice

“…This finding, in conjunction with evidence that other ABC family transporters also convey Aβ (12,13,15,16,18), implicates this family of molecules in cerebral Aβ export impairments in AD patients (4). Our results identify ABCC1 in particular as a potential target for impeding the pathogenesis of Aβ proteopathies such as AD and CAA.…”

“…The principal known mechanisms that contribute to the elimination of Aβ are degradation (by enzymes, the proteasome complex, and autophagy) (5,6), active, receptormediated transcytotic transport across the blood-brain barrier by LRP1 and RAGE, and by perivascular drainage of the extracellular fluid (7)(8)(9)(10)(11). In addition, 3 members of the ATP-binding cassette transporter family -ABCA1, ABCB1, and ABCG2 -have been shown to export Aβ (12)(13)(14)(15)(16)(17)(18). Members of different ABC transporter subfamilies exhibit different export kinetics for specified substrates (19,20).…”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…Ezáltal igazolódott e transzporterek szerepe az amiloid plakkok lerakódásának regulálásában. Több tanulmány igazolta a vér-agy gát endothelsejtjeinek apicalis felszínén a P-gp-expresszió szignifikáns csökkenését a természetes öregedési folyamattal párhuzamosan [55][56][57][58][59]. Mindezen megfigyelések alapján megfontolandó stratégia a P-gp-expresszió fokozása, illetve a transzporter aktiválása az időskori Alzheimer-kór megelőzésében.…”