Open AccessAn Anti-Parkinson’s Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-β Generation and γ-Secretase Activity
Author(s) -
Jing Lü,
Jin Cui,
Xiaohang Li,
Xin Wang,
Yue Zhou,
Wuyi Yang,
Ming Chen,
Jing Zhao,
Gang Pei
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0166415
Subject(s) - gene knockdown , presenilin , adenosine a2a receptor , medicine , pharmacology , amyloid precursor protein , amyloid precursor protein secretase , neuroscience , microbiology and biotechnology , receptor , alzheimer's disease , biology , cell culture , disease , adenosine receptor , agonist , genetics
γ-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of Aβ which is associated with Alzheimer’s disease (AD). Here we identified that an anti-Parkinson’s disease drug, Istradefylline, could enhance Aβ generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of Aβ 42 was detected in the cortex of APP/PS1 mouse after chronic treatment with Istradefylline. Istradefylline promoted the activity of γ-secretase which could lead to increased Aβ production. These effects of Istradefylline were reduced by the knockdown of A 2A R but independent of A 2A R-mediated G protein- or β-arrestin-dependent signal pathway. We further observed that A 2A R colocalized with γ-secretase in endosomes and physically interacted with the catalytic subunit presenilin-1 (PS1). Interestingly, Istradefylline attenuated the interaction in time- and dosage-dependent manners. Moreover the knockdown of A 2A R which in theory would release PS1 potentiated both Aβ generation and γ-secretase activity. Thus, our study implies that the association of A 2A R could modulate γ-secretase activity. Istradefylline enhance Aβ generation and γ-secretase activity possibly via modulating the interaction between A 2A R and γ-secretase, which may bring some undesired effects in the central nervous system (CNS).