African-Mandenka APP mutant protects from neurodegeneration in Alzheimer's disease model

BIGNANTE A, HEREDIA F, ZAMPONI E, PINOTTI D, HELGUERA P AND LORENZO A.

Puerto Varas

Congreso; XXVII Reunión Anual de la Sociedad de Biología Celular de Chile; 2013

Sociedad de Biología Celular de Chile

Alzheimer´s disease (AD) is a neurodegenerative disorder that mainly affects neocortical and limbic areas. The degenerative process is preceded and accompanied by Amyloide β (Aβ) aggregation and deposition. Aβ is a 40 and 43 aminoacide peptide with a natural propensity to self-assembly. The generation of multimeric Aβ-assemblies promotes neuronal dysfunction an toxicity, and presumably triggers the cognitive dysfunction in AD (Yankner & Lu, 2009; Mucke & Selkoe, 2012). Aβ is derived from the metabolic processing of the Amyloide β Precursor Protein (APP), a transmembrane protein intimately related with AD because it is the only resource of Aβ and pathogenic mutations in App cause genetic forms of AD (Bignante et al., 2013). The pathogenic mechanism of APP mutations predispose to Aβ-aggregation through diverse molecular mechanisms. Transgenic mice overexpressing pathogenic forms of APP develop senil plaques similar to AD patients, and show a certain grade of neuronal degeneration and cognitive deficit (reviewed by Spires & Hyman, 2005). The neurotoxic mechanism of Aβ remains elusive. Previous evidences from our group suggest that APP mediates Aβ-neurodegeneration through heterotrimeric Go protein (Lorenzo et al., 2000; Heredia et al., 2004; Sola Vigo et al., 2009; Kedikian et al., 2010). Previous studies indicate that replacement of the histidines doblete at positions 657 and 658 of APP by glycine and proline (APPHH/GP) alters the interaction/signaling of APP with heterotrinmeric Go (Nishimoto et al., 1993; Brouillet et al., 1999). In a recent study, a new non-pathogenic mutation on App was found in a neurologically sane subject from the African-Mandenka etnia (Guerreiro et al., 2010) . Interestingly, the mutation causes the substitution of histidine 658 by proline within the Go-interaction domain of APP. In the present work, we used in vitro experimental models of AD to address the pathophysiological significanse of the African-Mandenka APP mutation. Our data suggest that the the African-Mandenka APP mutation might have a dominat-negative effect preventing APP-Go mediated toxicity of Aβ . This observation would open new avenues for the the development of rational therapies for AD.