ROLE OF APP/GO PROTEIN Gbeta-gamma COMPLEX SIGNALING ON Amyloid Beta NEURODEGENERATION IN ALZHEIMER´S DISEASE MODELS.

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

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC

Deposition of amyloid-beta peptides (Abeta) causes neurodegeneration in Alzheimer?s disease (AD). Abeta is generated by regulated proteolysis of the amyloid precursor protein (APP). However, the involvement of APP, beyond its role as source of Abeta, in the mechanism of Abeta-induced degeneration remains elusive. Methods. FRET and co-immunoprecipitation were performed in primary hippocampal cultures and HEK293T in order to identify the effect of Abeta on APP and Go interaction. The physiopathological relevance of APP and Go signaling in Abeta 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 Abeta assemblies enhance APP and Go interaction (p < 0.001). APP overexpression renders hippocampal neurons vulnerable to Abeta-toxicity by a mechanism that requires Go-Gbeta-gamma signaling and p38-MAPK activation (p<0.05). We used gallein, a pharmacological inhibitor of Gbeta-gamma complex, to demonstrate that the activation of Go protein Gbeta-gamma complex mediates Abeta-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 Abeta assemblies (p < 0.05). Gallein also inhibited Abeta-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-Gbeta-gamma complex is a signaling hub potentially relevant for developing therapies for halting Abeta-degeneration and cognitive dysfunction in AD based on a molecular disease mechanism. Keywords. Alzheimer, Abeta, APP, Go protein, Gbeta-gamma complex, degeneration, tau phosphorylation, gallein, p38 MAPK, 3xTg-AD.