APP/Go protein Gbγ-complex signaling mediates Aβ degeneration and cognitive impairment in Alzheimer's disease models

Deposition of amyloid-beta (A beta), the proteolytic product of the amyloid precursor protein (APP), might cause neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the direct involvement of APP in the mechanism of A beta-induced degeneration in AD remains on debate. Here, we analyzed the interaction of APP with heterotrimeric Go protein in primary hippocampal cultures and found that A beta deposition dramatically enhanced APP-Go protein interaction in dystrophic neurites. APP overexpression rendered neurons vulnerable to A beta toxicity by a mechanism that required Go-G beta gamma complex signaling and p38emitogen-activated protein kinase activation. Gallein, a selective pharmacological inhibitor of G beta gamma complex, inhibited A beta-induced dendritic and axonal dystrophy, abnormal tau phosphorylation, synaptic loss, and neuronal cell death in hippocampal neurons expressing endogenous protein levels. In the 3xTg-AD mice, intrahippocampal application of gallein reversed memory impairment associated with early A beta pathology. Our data provide further evidence for the involvement of APP/Go protein in A beta-induced degeneration and reveal that G beta gamma complex is a signaling target potentially relevant for developing therapies for halting A beta degeneration in AD. (C) 2017 Elsevier Inc. All rights reserved.