ROLE OF APP/GO PATHWAY IN NEUROTOXICITY INDUCED BY AΒ AND ITS RELEVANCE IN ALZHEIMER DISEASE.

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Amyloid beta (Aβ) plays a central role in neurodegenerave process of Alzheimer disease (AD). However, neurotoxic mechanisms of Aβ are sll a maer of debate. Our laboratory works on the hypothesis that Aβ precursor protein (APP) is an atypical G protein coupled receptor (aGPCR) able to mediate the neurotoxic effect of Aβ through Go protein acvaon. Using cellular models characterized APP and Goα interacon through co-immunoprecipitaon, immunofluorescence and FRET, and found that Aβ increases APP and Go binding. The funconal role of APP/Go interacon in Aβ toxicity was analyzed through overexpression of both proteins in hippocampal primary cultures ulizing genecs and pharmacological tools. Data indicate that acvaon of APP/Go pathway induced by Aβ generates neuronal toxicity dependent of complex Gβγ signaling and subsequent p38-MAPK acvaon. Physiopathogenic role of Go-Gβγ acvaon by Aβ was analyzed in mature hippocampal cultures expressing endogen levels of proteins and found that synapc loss, neuric dystrophy abnormal tau phosphorylaon and neuronal death induced by Aβ are reverted by a pharmacological inhibion of Gβγ. All this evidence reveals a physiopathologic role of APP/Go pathway in the neurodegeneraon that characterize the AD and suggests its potentiality for therapeutic develop.