SIRT1 Regulates Tau Expression and Tau Synaptic Pathology.
SIRT1 Regulates Tau Expression and Tau Synaptic Pathology.
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DOI：
10.3233/jad-215118
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Xiaomin Yin;Zheng Zhou;Yanyan Qiu;Xing Fan;Chenhao Zhao;Junze Bao;Chenxu Liu;Fei Liu;Wei Qi
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文献类型：
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作者：
Xiaomin Yin;Zheng Zhou;Yanyan Qiu;Xing Fan;Chenhao Zhao;Junze Bao;Chenxu Liu;Fei Liu;Wei Qi
背景技术淀粉样蛋白斑和神经原纤维缠结是阿尔茨海默病(AD)的两个病理标志。然而，与淀粉样蛋白斑和神经原纤维缠结相比，突触缺陷发生得更早，并且与认知能力下降的相关性更强。 tau 蛋白的错误定位是神经退行性变的早期标志，并且发生在聚集之前。 Sirtuin 1 型 (SIRT1) 是一种脱乙酰酶，作用于包括转录因子在内的蛋白质，与 AD 密切相关。目的 本研究调查了细胞和小鼠大脑中 SIRT1 与 tau 表达之间的关联。方法Western blot检测tau、SIRT1、C/EBPα、GAPDH蛋白水平。免疫荧光测定用于评估原代皮质神经元细胞中 tau 的定位。进行高尔基体染色以评估小鼠大脑中的树突棘形态。结果在本研究中，我们发现SIRT1通过转录因子C/EBPα在转录水平负向调节tau的表达。 SIRT1 活性的抑制限制了 tau 蛋白向神经突的分布。同时，在SIRT1+/-小鼠的大脑中也观察到树突棘形态的改变。结论 SIRT1可能是AD早期干预的潜在药物靶点。
BACKGROUND Amyloid plaques and neurofibrillary tangles are two pathological hallmarks of Alzheimer's disease (AD). However, synaptic deficits occur much earlier and correlate stronger with cognitive decline than amyloid plaques and neurofibrillary tangles. Mislocalization of tau is an early hallmark of neurodegeneration and precedes aggregations. Sirtuin type 1 (SIRT1) is a deacetylase which acts on proteins including transcriptional factors and associates closely with AD. OBJECTIVE The present study investigated the association between SIRT1 and tau expression in cells and in mice brains. METHODS Western blot was performed to detected tau, SIRT1, C/EBPα, and GAPDH protein levels. Immunological fluorescence assay was used to assess tau localization in primary cortical neuronal cells. Golgi staining was performed to evaluated dendritic spine morphology in mice brains. RESULTS In the present study, we found that SIRT1 negatively regulates expression of tau at the transcriptional level through transcriptional factor C/EBPα. Inhibition of the activity of SIRT1 limits the distribution of tau to the neurites. In the meantime, the alteration of dendritic spine morphology is also observed in the brains of SIRT1+/- mice. CONCLUSION SIRT1 may be a potential drug target for early intervention in AD.