Aβ40 reduces p-glycoprotein at the blood–brain barrier through the ubiquitin–proteasome pathway

Anika M.S. Hartz, Yu Zhong, Andrea Wolf, Harry LeVine, David Miller, Björn Bauer

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Failure to clear amyloid-β (Aβ) from the brain is in part responsible for Aβ brain accumulation in Alzheimer’s disease (AD). A critical protein for clearing Aβ across the blood–brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood–brain barrier in AD, which has been shown to be associated with Aβ brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nM Aβ40, Aβ40, aggregated Aβ40, and Aβ42. We observed that only Aβ40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose- and time-dependent manner. To identify the steps involved in Aβ-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin–proteasome system, and monitored P-gp protein expression, transport activity, and P-gpubiquitin levels. Thus, exposing brain capillaries to Aβ40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findingsmayprovide potential therapeutic targets within the blood–brain barrier to limit P-gp degradation in AD and improve Aβ brain clearance.

Original languageEnglish
Pages (from-to)1930-1941
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number6
DOIs
StatePublished - Feb 10 2016

Bibliographical note

Publisher Copyright:
© 2016 the authors.

Keywords

  • Alzheimer’s disease
  • Blood–brain barrier
  • P-glycoprotein
  • Transporter
  • Ubiquitin–proteasome system

ASJC Scopus subject areas

  • General Neuroscience

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