Caffeine,Through Adenosine A 3 Receptor-Mediated Actions,Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation

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 suppress AβPP internalization may decrease amyloidogenic processing of AβPP. Here we tested the hypothesis that caffeine decreases Aβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosine A₃ receptor (A₃R) antagonist as well as siRNA knockdown of A₃Rs 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 in AβPP protein levels in neuronal plasma membranes, increased surface expression of AβPP on neurons, and the A₃R 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 of AβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A₃R-mediated internalization of AβPP.