Mutations in the Go-interacting domain of APP protects neurons for amyloid beta toxicity

HEREDIA FLORENCIA; LORENZO ALFREDO

Congreso; XXVI Congreso Annual de la Sociedad Argentina de Investigación en Neurociencia.; 2011

Sociedad Argentina de Investigación en Neurociencia (SAN).

Amyloid beta (Aß) is a metabolic fragment of the Amyloid ß precursor protein (APP).Deposition of Aß in the brain and neuronal degeneration are characteristic hallmarks of Alzheimerís disease(AD).Our lab have previously showed that interaction of Aß with APP induce neurodegeneration by a mechanism that involves heterotrimeric Go protein activation,suggesting an Aß-receptor-like role of APP in neuronal degeneration.In this presentation,to further study the signaling mechanism involved in APP-dependent toxicity of Aß,we performed site directed mutagenesis in the APP-Go protein interaction domain.We found that these mutations abrogated the Aß toxicity.In addition,we found that overexpression of wild type Gαo subunit abolished the Aß toxicity in a dose dependent manner,suggesting that APP/Go-dependent toxicity of Aß is not mediated by Gαo subunit-signaling.Moreover,the overexpression of both,the c-terminal fragment of the ß adrenergic receptor-kinase(ß-ARK-CT)and a prenylation-deficient mutant form of Gß,inhibit APP-dependent toxicity of Aß.These results suggest that Aß toxicity in neurons requires interaction of APP with Go protein,and signaling is mediated by GßΎ subunit of Go protein.