Ateya Nabaa Hisham, Al-Taie Sarah F, Jasim Saade Abdalkareem, Uthirapathy Subasini, Chaudhary Kamlesh, Rani Pooja, Kundlas Mayank, Naidu K Satyam, Amer Nevin Adel, Ahmed Jawad Kadhim
Biotechnology Department, College of Applied Science, Fallujah University, Al-Fallujah, Iraq.
University of Baghdad, College of Science, Department of Biotechnology, Baghdad, Iraq.
Cell Biochem Biophys. 2025 Jun;83(2):1537-1553. doi: 10.1007/s12013-025-01670-0. Epub 2025 Jan 18.
Histone acetylation is the process by which histone acetyltransferases (HATs) add an acetyl group to the N-terminal lysine residues of histones, resulting in a more open chromatin structure. Histone acetylation tends to increase gene expression more than methylation does. In the central nervous system (CNS), histone acetylation is essential for controlling the expression of genes linked to cognition and learning. Histone deacetylases (HDACs), "writing" enzymes (HATs), and "reading" enzymes with bromodomains that identify and localize to acetylated lysine residues are responsible for maintaining histone acetylation. By giving animals HDAC inhibitors (HDACis), it is possible to intentionally control the ratios of "writer" and "eraser" activity, which will change the acetylation of histones. In addition to making the chromatin more accessible, these histone acetylation alterations re-allocate the targeting of "readers," including the transcriptional co-activators, cAMP response element-binding protein (CBP), and bromodomain-containing protein 4 (Brd4) in the CNS. Conclusive evidence has shown that HDACs slow down the progression of Alzheimer's disease (AD) by reducing the amount of histone acetylation, decreasing the activity of genes linked to memory, supporting cognitive decline and Amyloid beta (Aβ) protein accumulation, influencing aberrant tau phosphorylation, and promoting the emergence of neurofibrillary tangles (NFTs). In this review, we have covered the therapeutic targets and functions of HDACs that might be useful in treating AD.
组蛋白乙酰化是指组蛋白乙酰转移酶（HATs）将乙酰基添加到组蛋白N端赖氨酸残基上的过程，从而导致染色质结构更加开放。与甲基化相比，组蛋白乙酰化往往更能促进基因表达。在中枢神经系统（CNS）中，组蛋白乙酰化对于控制与认知和学习相关的基因表达至关重要。组蛋白去乙酰化酶（HDACs）、“书写”酶（HATs）以及能够识别并定位到乙酰化赖氨酸残基的含溴结构域“读取”酶，共同负责维持组蛋白乙酰化。通过给动物使用HDAC抑制剂（HDACis），可以有意控制“书写”和“擦除”活性的比例，进而改变组蛋白的乙酰化状态。除了使染色质更容易接近外，这些组蛋白乙酰化改变还会重新分配“读取器”的靶向，包括中枢神经系统中的转录共激活因子、环磷酸腺苷反应元件结合蛋白（CBP）和含溴结构域蛋白4（Brd4）。确凿证据表明，HDACs通过减少组蛋白乙酰化量、降低与记忆相关基因的活性、促进认知能力下降和淀粉样β（Aβ）蛋白积累、影响异常的tau磷酸化以及促进神经纤维缠结（NFTs）的出现，从而减缓阿尔茨海默病（AD）的进展。在本综述中，我们涵盖了HDACs可能对治疗AD有用的治疗靶点和功能。
