Proteasome inhibition protects blood–brain barrier P-glycoprotein and lowers Aβ brain levels in an Alzheimer’s disease model

Fluids and Barriers of the CNS

Research

Björn Bauer¹  Bryan J. Maloney²  Milica Vulin²  Yu Zhong²  Anika M. S. Hartz³ 

[1] Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center On Aging, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center On Aging, University of Kentucky, Lexington, KY, USA;Department of Pharmacology and Nutritional Sciences, University of Kentucky, 124 Healthy Kentucky Research Building 760 Press Avenue, 40508, Lexington, KY, USA;

关键词: Blood–Brain Barrier;    P-glycoprotein;    Alzheimer’s disease;    Ubiquitin–proteasome system;    Amyloid beta;    Clearance;   

DOI  :  10.1186/s12987-023-00470-z

 received in 2023-04-17, accepted in 2023-09-23,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLoss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.MethodsWe treated hAPP mice with the proteasome inhibitor BTZ or a combination of BTZ with the P-gp inhibitor cyclosporin A (CSA) for 2 weeks. Vehicle-treated wild-type (WT) mice were used as a reference for normal P-gp protein expression and transport activity. In addition, we used the opioid receptor agonist loperamide as a P-gp substrate in tail flick assays to indirectly assess P-gp transport activity at the blood–brain barrier in vivo. We also determined P-gp protein expression by Western blotting, measured P-gp transport activity levels in isolated brain capillaries with live cell confocal imaging and assessed Aβ plasma and brain levels with ELISA.ResultsWe found that 2-week BTZ treatment of hAPP mice restored P-gp protein expression and transport activity in brain capillaries to levels found in WT mice. We also observed that hAPP mice displayed significant loperamide-induced central antinociception compared to WT mice indicating impaired P-gp transport activity at the blood–brain barrier of hAPP mice in vivo. Furthermore, BTZ treatment prevented loperamide-induced antinociception suggesting BTZ protected P-gp loss in hAPP mice. Further, BTZ-treated hAPP mice had lower Aβ40 and Aβ42 brain levels compared to vehicle-treated hAPP mice.ConclusionsOur data indicate that BTZ protects P-gp from proteasomal degradation in hAPP mice, which helps to reduce Aβ brain levels. Our data suggest that the proteasome system could be exploited for a novel therapeutic strategy in AD, particularly since increasing Aβ transport across the blood–brain barrier may prove an effective treatment for patients.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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