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

Jing Lu; Jin Cui; Xiaohang Li; Xin Wang; Yue Zhou; Wenjuan Yang; Ming Chen; Jian Zhao; Gang Pei

doi:10.1371/journal.pone.0166415

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. eCollection 2016.

Authors

Jing Lu¹, Jin Cui^{1

2}, Xiaohang Li^{1

2}, Xin Wang^{1

2}, Yue Zhou¹, Wenjuan Yang^{1

2

3}, Ming Chen⁴, Jian Zhao⁵, 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.

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).

MeSH terms

Adenosine A2 Receptor Antagonists / adverse effects*
Amyloid Precursor Protein Secretases / genetics*
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / agonists
Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics*
Amyloid beta-Protein Precursor / metabolism
Animals
Cell Line
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Endosomes / drug effects
Endosomes / metabolism
Gene Expression Regulation
Humans
Mice
Mice, Transgenic
Neurons / cytology
Neurons / drug effects*
Neurons / metabolism
Neuroprotective Agents / adverse effects*
Peptide Fragments / agonists
Peptide Fragments / genetics
Peptide Fragments / metabolism
Presenilin-1 / genetics
Presenilin-1 / metabolism
Primary Cell Culture
Purines / adverse effects*
Receptor, Adenosine A2A / deficiency
Receptor, Adenosine A2A / genetics
Signal Transduction
beta-Arrestins / genetics
beta-Arrestins / metabolism

Substances

APP protein, human
Adenosine A2 Receptor Antagonists
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Neuroprotective Agents
Peptide Fragments
Presenilin-1
Purines
Receptor, Adenosine A2A
amyloid beta-protein (1-42)
beta-Arrestins
istradefylline
Amyloid Precursor Protein Secretases

Grants and funding

This research was supported by the Ministry of Science and Technology of China (2011CB910202), the National Natural Science Foundation of China (31371419), Science and Technology Commission of Shanghai Municipality (13401900600).