APP/Go protein Gβγ-complex signaling mediates Aβ degeneration and cognitive impairment in rat and human models of Alzheimer?s disease

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

Buenos Aires

Congreso; Alzheimer´s Association International Conference; 2018

Alzheimer´s Association

Depositionof Amyloid-β (Aβ), the proteolytic product of the amyloid precursor protein(APP), causes neurodegeneration and cognitive decline in Alzheimer?s disease(AD). However, the direct involvement of APP in the mechanism of Aβ-induceddegeneration in AD remains on debate. Here, we analyzed the interaction of APPwith heterotrimeric Go protein in rat primary hippocampal cultures usingFluorescent Resonance Energy Transfer (FRET) microscopy and found that Aβdeposition dramatically enhanced APP-Go protein interaction in dystrophicneurites. APP overexpression rendered neurons vulnerable to Aβ toxicity by amechanism that required Go-Gβγ complex signaling and p38 mitogen-activatedprotein kinase (p38-MAPK) activation. Gallein, a selective pharmacologicalinhibitor of Gβγ complex, inhibited Aβ-induced p38-MAPK activation, dendriticand axonal dystrophy, abnormal tau phosphorylation, synaptic loss, and neuronalcell death in rat hippocampal cultures expressing endogenous protein levels. Inthe 3xTg-AD mice, which evidence memory impairment associated with early Aβpathology, intrahippocampal application of gallein reversed the memory deficitin the new object recognition test. Characterization of APP-Go interaction inhuman neurons derived from induced pluripotent stem cells (iPSc) will also be presented.Our data provide compelling evidence for the involvement of APP/Go protein in Aβ-induceddegeneration and reveal that Gβγ complex is a signaling target potentially relevantfor developing therapies for halting Aβ degeneration in AD.