CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
Aging Cell. 2023 Aug;22(8):e13895. doi: 10.1111/acel.13895. Epub 2023 Jun 26.
Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER-mitochondria cross-talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl-H3 in AD human cortex, and increased HDAC2-3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aβ oligomers (AβO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER-Ca retention and mitochondrial Ca accumulation, mitochondrial depolarization and impaired ER-mitochondria cross-talk, as observed in 3xTg-AD mouse hippocampal neurons and AβO-exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial-associated ER membranes (MAM) in cells exposed to AβO upon Tac treatment, along with reduction in ER-mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER-mitochondria Ca transfer and mitochondrial Ca retention, while knockdown of HDAC3 decreased ER-Ca accumulation in AβO-treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM-related proteins, and reduced Aβ levels. These data demonstrate that Tac normalizes Ca signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac-mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER-mitochondria communication as a promising target for innovative therapeutics in AD.
几种分子机制已在阿尔茨海默病（AD）中被描述，包括受抑制的基因转录和线粒体及内质网（ER）功能障碍。在这项研究中，我们评估了抑制或敲低 I 类组蛋白去乙酰化酶（HDACs）对改善 AD 模型中 ER-线粒体串扰的潜在疗效。数据显示 AD 人皮质中 HDAC3 蛋白水平升高，乙酰化-H3 减少，MCI 人外周细胞、暴露于 Aβ寡聚体（AβO）的 HT22 鼠海马细胞和 APP/PS1 鼠海马中 HDAC2-3 增加。Tacedinaline（Tac，一种选择性 I 类 HDAC 抑制剂）拮抗了 3xTg-AD 鼠海马神经元和 AβO 暴露的 HT22 细胞中观察到的 ER-Ca 保留增加和线粒体 Ca 积累、线粒体去极化和 ER-线粒体串扰受损。我们进一步证明，在用 Tac 处理后，暴露于 AβO 的细胞中线粒体相关内质网（MAM）相关蛋白的 mRNA 水平降低，同时 ER-线粒体接触（MERCS）长度减少。HDAC2 沉默减少了 ER-线粒体 Ca 转移和线粒体 Ca 保留，而 HDAC3 敲低减少了 AβO 处理细胞中的 ER-Ca 积累。用 Tac（30mg/kg/天）治疗的 APP/PS1 小鼠也显示出与 MAM 相关蛋白的 mRNA 水平调节，并降低了 Aβ 水平。这些数据表明，Tac 使 AD 海马神经细胞中线粒体和 ER 之间的 Ca 信号正常化，涉及这两个细胞器之间的连接。Tac 介导的 AD 改善是通过调节 MAM 中的蛋白质表达实现的，在 AD 细胞和动物模型中都观察到了这种调节。数据支持 ER-线粒体通讯的转录调控作为 AD 创新治疗的有前途的靶点。
