4.5 Article

Tubastatin A/ACY-1215 Improves Cognition in Alzheimer's Disease Transgenic Mice

期刊

JOURNAL OF ALZHEIMERS DISEASE
卷 41, 期 4, 页码 1193-1205

出版社

IOS PRESS
DOI: 10.3233/JAD-140066

关键词

Alzheimer's disease; amyloid; autophagy; histone deacetylase (HDAC); tau

资金

  1. Doctorial Innovation Fund of Peking Union Medical College [2012-1001-003]

向作者/读者索取更多资源

Histone deacetylase 6 (HDAC6) is currently being discussed as a promising therapeutic target for the treatment of Alzheimer's disease (AD). Mounting evidence indicates that increased HDAC6 expression may contribute to AD-associated neurodegeneration, although beneficial effects have also been identified. In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-beta (A beta) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of A beta and hyperphosphorylated tau. Further, the decreased hyperphosphorylated tau and increased tubulin acetylation may account for the improved microtubule stability in AD mice after tubastatin A/ACY-1215 treatment. These preclinical results support the detrimental role of HDAC6 in AD, and offer prospective approaches for using tubastatin A/ACY-1215 as potential therapeutic strategy for AD.

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