Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent ß-amyloid generation.
Cell
; 147(3): 615-28, 2011 Oct 28.
Article
en En
| MEDLINE
| ID: mdl-22036569
ABSTRACT
Assemblies of ß-amyloid (Aß) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The generation of Aß is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene Arc is required for activity-dependent generation of Aß. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both hebbian and non-hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Aß load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypothesize that Arc participates in the pathogenesis of AD.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Endosomas
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Precursor de Proteína beta-Amiloide
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Transporte de Proteínas
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Proteínas del Citoesqueleto
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Enfermedad de Alzheimer
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Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos