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

  • PLoS One. 2016 Nov 11;11(11):e0166415. doi: 10.1371/journal.pone.0166415.
Jing Lu  1 ,  Jin Cui  1  2 ,  Xiaohang Li  1  2 ,  Xin Wang  1  2 ,  Yue Zhou  1 ,  Wenjuan Yang  1  2  3 ,  Ming Chen  4 ,  Jian Zhao  5 ,  Gang Pei  1  6
Affiliations
  • 1. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2. Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
  • 4. Chemical Biology Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 5. Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
  • 6. School of Life Science and Technology, Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China.
PMID: 27835671 DOI: 10.1371/journal.pone.0166415
Abstract

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 Aβ42 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 A2AR but independent of A2AR-mediated G protein- or β-arrestin-dependent signal pathway. We further observed that A2AR 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 A2AR which in theory would release PS1 potentiated both Aβ generation and γ-secretase activity. Thus, our study implies that the association of A2AR could modulate γ-secretase activity. Istradefylline enhance Aβ generation and γ-secretase activity possibly via modulating the interaction between A2AR and γ-secretase, which may bring some undesired effects in the central nervous system (CNS).

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