Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation

Shanshan Li, Nicholas H. Geiger, Mahmoud L. Soliman, Liang Hui, Jonathan D. Geiger, Xuesong Chen

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppressAβPP internalization may decrease amyloidogenic processing ofAβPP. Here we tested the hypothesis that caffeine decreasesAβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosineA3 receptor (A3R) antagonist as well as siRNAknockdown ofA3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases inAβPP protein levels in neuronal plasma membranes, increased surface expression ofAβPP on neurons, and theA3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression ofAβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.

Original languageEnglish (US)
Pages (from-to)73-83
Number of pages11
JournalJournal of Alzheimer's Disease
Volume47
Issue number1
DOIs
StatePublished - 2015

Keywords

  • Adenosine A receptor
  • Alzheimer's disease
  • Amyloid-β
  • Amyloid-β protein precursor
  • Caffeine
  • Endocytosis
  • LDL cholesterol

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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