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

Frontiers in Aging Neuroscience
Anika M S HartzBjörn Bauer

Abstract

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 reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Aβ40 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 immun...Continue Reading

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Citations

Nov 22, 2019·The FEBS Journal·Amanda B ChaiIngrid C Gelissen
Feb 6, 2019·Fluids and Barriers of the CNS·Richard F KeepLester R Drewes
Aug 17, 2019·Frontiers in Aging Neuroscience·Franciska Erdő, Péter Krajcsi
Apr 25, 2020·Frontiers in Cellular Neuroscience·Hallel C ParaisoI-Chen Yu
Oct 21, 2018·Fluids and Barriers of the CNS·Stephen B Hladky, Margery A Barrand
Oct 7, 2020·FEBS Letters·Richard CallaghanAnika M S Hartz
Nov 27, 2020·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Monica Gireud-GossAkihiko Urayama
Dec 24, 2019·Acta Pharmaceutica Sinica. B·Yuhua LiHuichang Bi
Dec 5, 2020·Neurotrauma Reports·Sydney M VitaBernadette E Grayson
Jan 2, 2021·International Journal of Molecular Sciences·Amanda B ChaiIngrid C Gelissen

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Methods Mentioned

BETA
ubiquitination
transgenic
confocal microscopy
ELISA
electrophoresis
immunoprecipitation
imaging techniques
ELISAs

Key Resources (RRID) Mentioned

SCR_002798
IMSR_TAC
AB_306371
AB_298985
AB_298987
AB_2234877
AB_303947
AB_442855
AB_10860339
AB_795165

Software Mentioned

Image J
ImageJ
ProteinSimple
[UNK]
GraphPad Prism
Image Lab

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