An Anti-Parkinson’s Disease Drug via Targeting Adenosine A(2A) Receptor Enhances Amyloid-β Generation and γ-Secretase Activity

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).