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

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy.
Exp Neurol. 2016 Jun 21;283(Pt A):213-223
Authors: Hu Q, Ren X, Liu Y, Li Z, Zhang L, Chen X, He C, Chen JF
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 A2A receptor (A2AR) 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 A2AR expression which was closely co-localized with pSer129 α-Syn-rich inclusions in neurons and glial cells of hippocampus. Importantly, by abolishing aberrant A2AR signaling triggered by mutant α-Syn, genetic deletion of A2ARs 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 A2AR signaling as a critical pathogenesis mechanism of sy...

Source: Experimental Neurology - June 20, 2016 Category: Neurology Authors: Hu Q, Ren X, Liu Y, Li Z, Zhang L, Chen X, He C, Chen JF Tags: Exp Neurol Source Type: research