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

gamma-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of A beta which is associated with Alzheimer's disease (AD). Here we identified that an anti-Parkinson's disease drug, Istradefylline, could enhance A beta generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of A beta 42 was detected in the cortex of APP/PS1 mouse after chronic treatment with Istradefylline. Istradefylline promoted the activity of gamma-secretase which could lead to increased A beta production. These effects of Istradefylline were reduced by the knockdown of A(2A)R but independent of A(2A)R-mediated G protein- or beta-arrestin-dependent signal pathway. We further observed that A(2A)R colocalized with gamma-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 A beta generation and gamma-secretase activity. Thus, our study implies that the association of A(2A)R could modulate gamma-secretase activity. Istradefylline enhance A beta generation and gamma-secretase activity possibly via modulating the interaction between A(2A)R and gamma-secretase, which may bring some undesired effects in the central nervous system (CNS).