Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß.
J Cell Biol
; 209(3): 419-33, 2015 May 11.
Article
em En
| MEDLINE
| ID: mdl-25963821
ABSTRACT
Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid ß (Aß) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aß oligomers. Relevance of these findings to naturally secreted Aß and mechanisms underlying tau's enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aß1-42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3ß (GSK3ß) activity or expression also abolished Aß-induced transport deficits. Tau ablation prevented Aß-induced GSK3ß activation. Thus, tau allows Aß oligomers to inhibit axonal transport through activation of GSK3ß, possibly by facilitating aberrant neuronal activity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Transporte Axonal
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Peptídeos beta-Amiloides
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Proteínas tau
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Quinase 3 da Glicogênio Sintase
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Doença de Alzheimer
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article