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Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production.
Dimitrov, Mitko; Alattia, Jean-René; Lemmin, Thomas; Lehal, Rajwinder; Fligier, Andrzej; Houacine, Jemila; Hussain, Ishrut; Radtke, Freddy; Dal Peraro, Matteo; Beher, Dirk; Fraering, Patrick C.
Afiliação
  • Dimitrov M; Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH1015 Lausanne, Switzerland.
Nat Commun ; 4: 2246, 2013.
Article em En | MEDLINE | ID: mdl-23907250
Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical γ-secretase modulators affect the processing of APP by the γ-secretase complex and the production of the amyloid-beta peptide Aß42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both γ- and ε-cleavage sites, by raising the Aß42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to γ-secretase modulators, which shift Aß42 production towards the shorter Aß38, but unequivocally spare the ε-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its γ-site, modifying at the same time, the solvation of the ε-site.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Precursor de Proteína beta-Amiloide / Secretases da Proteína Precursora do Amiloide / Doença de Alzheimer / Mutação Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Precursor de Proteína beta-Amiloide / Secretases da Proteína Precursora do Amiloide / Doença de Alzheimer / Mutação Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article