Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease.
Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease.
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2021
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寻找阿尔茨海默病（AD）的疾病修饰治疗的努力在很大程度上是不成功的。相对缺乏进展和与年龄相关的AD发病率表明，调节衰老本身可能是一种有用的替代治疗方法。旨在预防或逆转衰老的治疗应有效预防或逆转痴呆和与进行性AD相关的病理学。神经元基因表达的表观遗传失调随着年龄的增长而发生，在细胞内稳态中传播缺陷。表观遗传过程的调节剂，如组蛋白脱乙酰酶（HDAC），是有据可查的，并可能代表有前途的治疗靶点。HDAC活性随着年龄和AD而变得失调。一个有趣的概念是，HDAC抑制有效地阻止AD病理学更广泛地测量，解决的概念，纠正稳态基因表达可能是在疾病开始的最早阶段改善AD发病机制的关键步骤。HDAC抑制剂靶向与衰老和AD神经病理学相关的几种途径，包括突触功能丧失、线粒体功能障碍、氧化应激增加和自噬活性降低。由于许多基因的转录水平随着年龄的增长而降低，因此通过HDAC抑制恢复其转录活性可以预防或延迟神经功能的年龄相关下降，并提供治疗AD的途径。
Efforts to find disease-modifying treatments for Alzheimer’s disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD.