An Anti-Parkinson's Disease Drug via Targeting Adenosine A2A 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 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).
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Jing
J
Lu
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Jin
J
Cui
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Xiaohang
X
Li
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Xin
X
Wang
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Yue
Y
Zhou
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.|Graduate School, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.|School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China.
Wenjuan
W
Yang
Chemical Biology Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Ming
M
Chen
Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Jian
J
Zhao
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.|School of Life Science and Technology, Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China.
Gang
G
Pei
D058917:Adenosine A2 Receptor Antagonists / Q000009:adverse effects*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000009:adverse effects*; D010446:Peptide Fragments / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011687:Purines / Q000009:adverse effects*; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D000071557:beta-Arrestins / Q000235:genetics / Q000378:metabolism
C545487:APP protein, human; D058917:Adenosine A2 Receptor Antagonists; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D053764:Presenilin-1; D011687:Purines; D043705:Receptor, Adenosine A2A; C075222:amyloid beta-protein (1-42); D000071557:beta-Arrestins; C111599:istradefylline; D053829:Amyloid Precursor Protein Secretases