P2‐330: Protection of excitatory synapses by DHA through preserving function of NMDA‐Tiam1‐PAK signal pathway in Alzheimer models
| Autor: | Greg M. Cole, Walter Beech, Sally A. Frautschy, Fusheng Yang, Oliver J. Ubeda, Ma Qiulan, Cory Chen, Yongle Zhao, Mher Alaverdyan, Dana J. Gant |
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| Rok vydání: | 2010 |
| Předmět: |
Regulation of gene expression
Epidemiology medicine.drug_class Health Policy Histone deacetylase inhibitor Long-term potentiation Biology Psychiatry and Mental health Cellular and Molecular Neuroscience Trichostatin A Histone Developmental Neuroscience medicine biology.protein Neurology (clinical) Epigenetics Histone deacetylase Fear conditioning Geriatrics and Gerontology Neuroscience medicine.drug |
| Zdroj: | Alzheimer's & Dementia. 6 |
| ISSN: | 1552-5279 1552-5260 |
| Popis: | Background: 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 Alzheimer’s disease (AD) etiology. 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. Methods: Westen blot, LTP and contextual fear conditioning Results: 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), rescued the defect in CA3-CA1 LTP in slices from APP/PS1 mice. Moreover, TSA administration prior to training rescued both the defect in acetylated H4 levels and contextual freezing to wildtype values. This effect was likley due to amyloid-beta elevation as TSA rescued also the amyloid-beta induced defect in contextual fear memory. Conclusions: 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. |
| Databáze: | OpenAIRE |
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