Aberrant adenosine A(2A) receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

作者：Hu, Qidi; Ren, Xiangpeng^*; Liu, Ya; Li, Zhihui; Zhang, Liping; Chen, Xingjun; He, Chaoxiang; Chen, Jiang-Fan^*

来源：Experimental Neurology, 2016, 283: 213-223.

DOI：10.1016/j.expneurol.2016.05.040

• alpha-Synuclein
• Adenosine A(2A) receptor
• Hippocampus
• Synucleinopathy

Synucleinopathy is characterized by abnormal accumulation of misfolded alpha-synuclein (alpha-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 alpha-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 alpha-Syn fibrils triggered a striking and selective induction of A(2A)R expression which was closely co-localized with pSer129 alpha Syn-rich inclusions in neurons and glial cells of hippocampus. Importantly, by abolishing aberrant A(2A)R signaling triggered by mutant alpha-Syn, genetic deletion of A(2A)Rs blunted a cascade of pathological events leading to synucleinopathy, including pSer129 ce-Syn-rich and p62-positive aggregates, NF-kappa B activation and astrogliosis, apoptotic neuronal cell death and working memory deficits without affecting motor activity. These findings define alpha-Syn-triggered aberrant A(2A)R signaling as a critical pathogenesis mechanism of synucleinopathy with dual controls of cognition and neurodegeneration by modulating alpha-Syn aggregates. Thus, aberrant A(2A)R signaling represents a useful biomarker as well as a therapeutic target of synucleinopathy.

• 出版日期2016-9
• 单位温州医科大学