Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer's disease
Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer's disease
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DOI：
10.1016/j.brainres.2013.04.059
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发表时间：
2013-06-26
期刊：
影响因子：
2.9
通讯作者：
Cai, Wen-Qing
中科院分区：
文献类型：
--
作者：
Jiang, Yu-Qing;Wang, Xiu-Li;Cai, Wen-Qing
阿尔茨海默病（AD）是最使人衰弱的神经退行性神经疾病之一，严重影响人们进行日常活动的能力。阿尔茨海默病是一种进行性且无法治愈的疾病，但分子研究已经开始揭示其背后的机制。免疫化学染色显示，与正常大鼠相比，AD大鼠小脑Purldnje细胞胞体明显减少。热休克蛋白70 （HSP70）在亨廷顿病和脊髓小脑共济失调（SCAs）中可防止聚谷氨酰胺聚集，并可缓解SCAs和帕金森病的症状。最近，在HSP70转基因大鼠中发现ad相关表型被抑制。然而，其他热休克蛋白的作用和热休克蛋白引发AD变化的机制尚不清楚。在本研究中，我们发现HSP60、-70和-90在AD大鼠小脑中的表达水平下调。此外，热休克因子1 （HSF1）作为热休克基因表达的关键转录因子，在AD大鼠小脑中显著降低。更有趣的是，将慢病毒载体HSF1注射到AD大鼠小脑内，可显著提高HSF1和HSP的表达水平，诱导浦肯野细胞体数量增加。我们的研究结果提供了新的证据，证明阿尔茨海默病大鼠HSPs的低表达依赖于HSF1的低表达，而HSF1的表达增加有助于阿尔茨海默病小脑浦肯野细胞缺乏症的逆转。因此，增加HSF1的表达是一种潜在的治疗AD的新策略。Elsevier B.V.出版
Alzheimer's disease (AD) is one of the most debilitating neurodegenerative nerve diseases, seriously affecting one's ability to carry out daily activities. AD is both progressive and incurable, but molecular studies have begun to shed light on the mechanisms that underlie it. Immunochemical staining showed that cell bodies of Purldnje cells in the cerebellum were significantly reduced in AD rats compared with normal rats. Heat shock protein 70 (HSP70) was found to prevent polyglutamine aggregation in Huntington's disease and spinocerebellar ataxias (SCAs) and to relieve symptoms in SCAs and Parkinson's disease. Recently, AD-related phenotypes were found to be suppressed in HSP70 transgenic rats. However, the effects of other HSPs and the mechanisms of HSP-triggered changes in AD are unknown. In this study, we found that expression levels of HSP60, -70, and -90 were downregulated in the cerebella of rats with AD. Furthermore, heat shock factor 1 (HSF1), a key transcription factor for the expression of HSP genes, was found to be greatly decreased in the cerebella of AD rats. Even more interesting, injection of lentivirus vector-HSF1 into the cerebella of AD rats significantly increased HSF1 and HSP expression levels and induced an increase in the number of Purkinje cell bodies. Our findings provide novel evidence that low expression of HSPs in AD rats is dependent on the low expression of HSF1, and increased expression of HSF1 contributes td the reversal of cerebellar Purkinje cell deficiency in AD. Therefore, increasing HSF1 expression is a potential new strategy for the treatment of AD. Published by Elsevier B.V.