APP/Go protein Gbg-complex signaling mediates Ab degeneration and cognitive impairment in Alzheimer?s disease models

INESTROSA NIBALDO; KRAWCZYK MARIA C; PONCE NICOLAS ERIC; BOCCIA MARIANO; MILLAN JULIETA; HEREDIA FLORENCIA; LORENZO ALFREDO; PIGINO GUSTAVO; MUSSO JULIANA; BIGNANTE ELENA ANAHI; BOCCIA MARIANO; INESTROSA NIBALDO; MILLAN JULIETA; KRAWCZYK MARIA C; HEREDIA FLORENCIA; PONCE NICOLAS ERIC; LORENZO ALFREDO; PIGINO GUSTAVO; MUSSO JULIANA; BIGNANTE ELENA ANAHI

NEUROBIOLOGY OF AGING

ELSEVIER SCIENCE INC

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

0197-4580

Deposition of amyloid-b (Ab), the proteolytic product of the amyloid precursor protein (APP), mightcause neurodegeneration and cognitive decline in Alzheimer?s disease (AD). However, the directinvolvement of APP in the mechanism of Ab-induced degeneration in AD remains on debate. Here, weanalyzed the interaction of APP with heterotrimeric Go protein in primary hippocampal cultures andfound that Ab deposition dramatically enhanced APP-Go protein interaction in dystrophic neurites. APPoverexpression rendered neurons vulnerable to Ab toxicity by a mechanism that required Go-Gbgcomplex signaling and p38emitogen-activated protein kinase activation. Gallein, a selective pharmacologicalinhibitor of Gbg complex, inhibited Ab-induced dendritic and axonal dystrophy, abnormal tauphosphorylation, synaptic loss, and neuronal cell death in hippocampal neurons expressing endogenousprotein levels. In the 3xTg-AD mice, intrahippocampal application of gallein reversed memory impairmentassociated with early Ab pathology. Our data provide further evidence for the involvement ofAPP/Go protein in Ab-induced degeneration and reveal that Gbg complex is a signaling target potentiallyrelevant for developing therapies for halting Ab degeneration in AD.