期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 18, 期 1, 页码 131-139出版社
IOS PRESS
DOI: 10.3233/JAD-2009-1134
关键词
Acetylation; Alzheimer's disease; HDACs; histone; long term potentiation
资金
- Alzheimer Disease Research Zenith [ZEN-07-58977]
- National Institutes of Health [R01 NS049442]
- United Kingdom Alzheimer's Research Trust Pilot Grant
- International Sephardic Educational Foundation (ISEF) Scholarship
- Lewis Family Trust Scholarship
- Sidney & Elizabeth Corob Charitable Trust Scholarship
- Charlotte and Yule Bogue Research Fellowships
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS049442] Funding Source: NIH RePORTER
Epigenetic mechanisms such as post-translational histone modifications are increasingly recognized for their contribution to gene activation and silencing in the brain. Histone acetylation in particular has been shown to be important both in hippocampal long-term potentiation (LTP) and memory formation in mice. The involvement of the epigenetic modulation of memory formation has also been proposed in neuropathological models, although up to now no clear-cut connection has been demonstrated between histone modifications and the etiology of Alzheimer's disease (AD). Thus, we have undertaken preclinical studies in the APP/PS1 mouse model of AD to determine whether there are differences in histone acetylation levels during associative memory formation. After fear conditioning training, levels of hippocampal acetylated histone 4 (H4) in APP/PS1 mice were about 50% lower than in wild-type littermates. Interestingly, acute treatment with a histone deacetylase inhibitor, Trichostatin A (TSA), prior to training rescued both acetylated H4 levels and contextual freezing performance to wild-type values. Moreover, TSA rescued CA3-CA1 LTP in slices from APP/PS1 mice. Based on this evidence, we propose the hypothesis that epigenetic mechanisms are involved in the altered synaptic function and memory associated with AD. In this respect, histone deacetylase inhibitors represent a new therapeutic target to effectively counteract disease progression.
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