APP/Go protein Gbetagamma-complex signaling mediates Abeta degeneration and cognitive impairment in Alzheimer's disease models.

BIGNANTE, ELENA A.; PONCE, NICOLAS E; HEREDIA FLORENCIA; MUSSO JULIANA; KRAWCZYK MARIA C; MILLAN JULIETA; PIGINO GUSTAVO; INESTROSA NIBALDO; BOCCIA MARIANO; LORENZO ALFREDO

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2017 vol. 64 p. 44 - 57

0197-4580

Deposition of Amyloid-β (Aβ), 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 Aβ-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 Aβ deposition dramatically enhanced APP-Go protein interaction in dystrophic neurites. APP-overexpression rendered neurons vulnerable to Aβ-toxicity by a mechanism that required Go-Gβγ complex signaling and p38-MAPK activation. Gallein, a selective pharmacological inhibitor of Gβγ complex, inhibited Aβ-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 Aβ-patology. Our data provide further evidence for the involvement of APP/Go protein in Aβ-induced degeneration, and reveal that Gβγ complex is a signaling target potentially relevant for developing therapies for halting Aβ-degeneration in AD.