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Elife ; 52016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27196744

RESUMO

Presenilin 1 (PS1) is an essential γ-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer's disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Aß production, the importance of other APP metabolites and γ-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with Gαs protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neurônios/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Animais , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Camundongos
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