Dataset Information

Preventing P-gp Ubiquitination Lowers A? Brain Levels in an Alzheimer's Disease Mouse Model.

ABSTRACT: One characteristic of Alzheimer's disease (AD) is excessive accumulation of amyloid-? (A?) in the brain. A? brain accumulation is, in part, due to a reduction in A? clearance from the brain across the blood-brain barrier. One key element that contributes to A? brain clearance is P-glycoprotein (P-gp) that transports A? from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs A? brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that A?40 triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these data, we show here that ubiquitinated P-gp levels in brain capillaries isolated from brain samples of AD patients are increased compared to capillaries isolated from brain tissue of cognitive normal individuals. We extended this line of research to in vivo studies using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576) that were treated with PYR41, a cell-permeable, irreversible inhibitor of the ubiquitin-activating enzyme E1. Our data show that inhibiting P-gp ubiquitination protects the transporter from degradation, and immunoprecipitation experiments confirmed that PYR41 prevented P-gp ubiquitination. We further found that PYR41 treatment prevented reduction of P-gp protein expression and transport activity levels and substantially lowered A? brain levels in hAPP mice. Together, our findings provide in vivo proof that the ubiquitin-proteasome system mediates reduction of blood-brain barrier P-gp in AD and that inhibiting P-gp ubiquitination prevents P-gp degradation and lowers A? brain levels. Thus, targeting the ubiquitin-proteasome system may provide a novel therapeutic approach to protect blood-brain barrier P-gp from degradation in AD and other A?-based pathologies.

SUBMITTER: Hartz AMS

PROVIDER: S-EPMC6028735 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Preventing P-gp Ubiquitination Lowers Aβ Brain Levels in an Alzheimer's Disease Mouse Model.

Hartz Anika M S AMS Zhong Yu Y Shen Andrew N AN Abner Erin L EL Bauer Björn B

Frontiers in aging neuroscience 20180626

One characteristic of Alzheimer's disease (AD) is excessive accumulation of amyloid-β (Aβ) in the brain. Aβ brain accumulation is, in part, due to a reduction in Aβ clearance from the brain across the blood-brain barrier. One key element that contributes to Aβ brain clearance is P-glycoprotein (P-gp) that transports Aβ from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aβ brain clearance. The mechanism responsible for reduce ...[more]

PMID: 29997495

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Dataset Information

Preventing P-gp Ubiquitination Lowers A? Brain Levels in an Alzheimer's Disease Mouse Model.

Publications

Preventing P-gp Ubiquitination Lowers Aβ Brain Levels in an Alzheimer's Disease Mouse Model.

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