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

HEREDIA, FLORENCIA; MILLÁN, JULIETA; BOCCIA, MARIANO M.; PONCE, NICOLÁS ERIC; KRAWCZYK, MARÍA C.; PONCE, NICOLÁS ERIC; INESTROSA, NIBALDO C.; KRAWCZYK, MARÍA C.; INESTROSA, NIBALDO C.; BIGNANTE, ELENA ANAHI; MUSSO, JULIANA; PIGINO, GUSTAVO F.; BIGNANTE, ELENA ANAHI; LORENZO, ALFREDO; MUSSO, JULIANA; PIGINO, GUSTAVO F.; LORENZO, ALFREDO; HEREDIA, FLORENCIA; MILLÁN, JULIETA; BOCCIA, MARIANO M.

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

Lugar: Amsterdam; Año: 2018 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-mitogen-activated protein kinase 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 pathology. 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.