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

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).

• Authors: Jing Lu, Jin Cui, Xiaohang Li, Xin Wang, Yue Zhou, Wenjuan Yang, Ming Chen, Jian Zhao, Gang Pei
• Journal: PloS one (PLoS One) Vol. 11 Issue 11 Pg. e0166415 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27835671 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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