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1.
Cell Rep ; 27(5): 1345-1355.e6, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31042463

RESUMO

Amyloid precursor protein (APP) and its metabolites play key roles in Alzheimer's disease (AD) pathophysiology. Whereas short amyloid-ß (Aß) peptides derived from APP are pathogenic, the APP holoprotein serves multiple purposes in the nervous system through its cell adhesion and receptor-like properties. Our studies focused on the signaling mediated by the APP cytoplasmic tail. We investigated whether sustained APP signaling during brain development might favor neuronal plasticity and memory process through a direct interaction with the heterotrimeric G-protein subunit GαS (stimulatory G-protein alpha subunit). Our results reveal that APP possesses autonomous regulatory capacity within its intracellular domain that promotes APP cell surface residence, precludes Aß production, facilitates axodendritic development, and preserves cellular substrates of memory. Altogether, these events contribute to strengthening cognitive functions and are sufficient to modify the course of AD pathology.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Memória , Neurogênese , Transdução de Sinais , Precursor de Proteína beta-Amiloide/química , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Células Cultivadas , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Domínios Proteicos
2.
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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