An Anti-Parkinson's Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-? Generation and ?-Secretase Activity.

ABSTRACT: ?-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of A? which is associated with Alzheimer's disease (AD). Here we identified that an anti-Parkinson's disease drug, Istradefylline, could enhance A? generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of A?42 was detected in the cortex of APP/PS1 mouse after chronic treatment with Istradefylline. Istradefylline promoted the activity of ?-secretase which could lead to increased A? production. These effects of Istradefylline were reduced by the knockdown of A2AR but independent of A2AR-mediated G protein- or ?-arrestin-dependent signal pathway. We further observed that A2AR colocalized with ?-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 A2AR which in theory would release PS1 potentiated both A? generation and ?-secretase activity. Thus, our study implies that the association of A2AR could modulate ?-secretase activity. Istradefylline enhance A? generation and ?-secretase activity possibly via modulating the interaction between A2AR and ?-secretase, which may bring some undesired effects in the central nervous system (CNS).

SUBMITTER: Lu J 

PROVIDER: S-EPMC5106031 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature