Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy.

Abstract Synucleinopathy is characterized by abnormal accumulation of misfolded α-synuclein (α-Syn)-positive cytoplasmic inclusions and by neurodegeneration and cognitive impairments, but the pathogenesis mechanism of synucleinopathy remains to be defined. Using a transmission model of synucleinopathy by intracerebral injection of preformed A53T α-Syn fibrils, we investigated whether aberrant adenosine A 2A receptor (A 2A R) signaling contributed to pathogenesis of synucleinopathy. We demonstrated that intra-hippocampal injection of preformed mutant α-Syn fibrils triggered a striking and selective induction of A 2A R expression which was closely co-localized with pSer129 α- Syn -rich inclusions in neurons and glial cells of hippocampus. Importantly, by abolishing aberrant A 2A R signaling triggered by mutant α-Syn, genetic deletion of A 2A Rs blunted a cascade of pathological events leading to synucleinopathy, including pSer129 α- Syn -rich and p62-positive aggregates, NF-κB activation and astrogliosis, apoptotic neuronal cell death and working memory deficits without affecting motor activity. These findings define α- Syn -triggered aberrant A 2A R signaling as a critical pathogenesis mechanism of synucleinopathy with dual controls of cognition and neurodegeneration by modulating α-Syn aggregates. Thus, aberrant A 2A R signaling represents a useful biomarker as well as a therapeutic target of synucleinopathy.