Role of APP/Go protein Gβγ complex signaling on Aβ neurodegeneration in Alzheimer´s disease models

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

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

ROLE OF APP/GO PROTEIN Gβγ COMPLEX SIGNALING ON Aβ NEURODEGENERATION IN ALZHEIMER´S DISEASE MODELS.Deposition of amyloid-β peptides (Aβ) causes neurodegeneration in Alzheimer?s disease (AD). Aβ is generated by regulated proteolysis of the amyloid precursor protein (APP). However, the involvement of APP, beyond its role as source of Aβ, in the mechanism of Aβ-induced degeneration remains elusive. Methods. FRET and co-immunoprecipitation were performed in primary hippocampal cultures and HEK293T in order to identify the effect of Aβ on APP and Go interaction. The physiopathological relevance of APP and Go signaling in Aβ neurodegeneration was determined by analyzing neuronal dystrophy, tau phosphorylation and neuronal death in primary hippocampal cultures and by assessment of memory performance in the 3xTgAD mice using the novel object recognition (NOR) test. Results. We found that toxic Aβ assemblies enhance APP and Go interaction (p < 0.001). APP overexpression renders hippocampal neurons vulnerable to Aβ-toxicity by a mechanism that requires Go-Gβγ signaling and p38-MAPK activation (p<0.05). We used gallein, a pharmacological inhibitor of Gβγ complex, to demonstrate that the activation of Go protein Gβγ complex mediates Aβ-induced p38-MAPK activation and neuronal degeneration (p < 0.001). In mature hippocampal cultures expressing endogenous proteins, treatment with gallein and PD503208 reduced neuronal degeneration, tau phosphorylation at the PHF-1 epitope induced by toxic Aβ assemblies (p < 0.05). Gallein also inhibited Aβ-induced synaptic loss in hippocampal cultures (p < 0.001). Finally, in the 3xTgAD mice, an AD model, acute application of gallein in dorsal hippocampus restores memory performance in the NOR test (p < 0.05). Conclusions. Our data reveal that APP/Go-Gβγ complex is a signaling hub potentially relevant for developing therapies for halting Aβ-degeneration and cognitive dysfunction in AD based on a molecular disease mechanism. Keywords. Alzheimer, Aβ, APP, Go protein, Gβγ complex, degeneration, tau phosphorylation, gallein, p38 MAPK, 3xTg-AD.