靶向抑制HDAC3调控阿尔茨海默病记忆-神经环路重塑的机制研究

Entorhinal cortex-hippocampal neural circuits are closely related to the memory function in Alzheimer's disease (AD). Preliminary studies demonstrated that H3 and H4 histone acetylation levels in hippocampus of APP/PS1 mice were lower than that of wide-type group. Knocking-down histone deacetylase 3 (HDAC3) could increase histone acetylation levels and improve learning and memory function of the APP/PS1 mice, suggesting that histone acetylation could regulate the remodeling of the memory-neural circuits. This study will mainly focus on the following two parts: 1) to confirm that inhibition of HDAC3 exerts neuroprotective effects and to explore the memory-neural circuits specific genes of AD regulated by HDAC3 inhibition; and 2) to identify the effects of acetylation of specific targets to the regulation of AD memory-neuronal circuits by behavioristics, pathology and molecular biology. For the first time this project have demonstrated the relation of the acetylation homeostasis and remoding of the memory-neural circuits of AD. In addition, this study will investigate the molecular mechanisms of the remolding of memory -neural circuits of AD, which would promote the researches on the remodeling of memory neural circuits and provide new targets for early diagnosis and treatment for AD.

内嗅皮层-海马神经环路与Alzheimer's disease（AD）的记忆功能密切相关。前期研究发现，APP/PS1小鼠海马区H3和H4组蛋白乙酰化水平低于正常组，而特异性干扰HDAC3可提高组蛋白乙酰化水平，改善APP/PS1小鼠的学习和记忆功能，提示组蛋白乙酰化可调控AD记忆-神经环路的重塑。本课题利用行为学、病理学、分子生物学等技术进行以下体内外研究：1）靶向抑制HDAC3具有神经保护作用，进一步探讨受其调控的AD记忆-神经环路的特异性基因群；2）特定基因群的乙酰化对AD记忆-神经环路重塑的影响。本项目首次将AD的记忆-神经环路乙酰化稳态与环路的重塑相联系，阐明AD记忆-神经环路重塑的分子调控机制；对AD记忆-神经环路重塑的基础研究具有一定贡献，同时对临床早期诊断和治疗提供新的靶点。

阿尔茨海默病（Alzheimer’s disease，AD）是临床最常见的老年痴呆类型，其特征性病理改变包括b-淀粉样蛋白（beta-amyloid，Ab）沉积形成的淀粉样斑块和高度磷酸化的tau蛋白组成的神经纤维缠结，目前病因尚不明确，而突触可塑性受损是AD的早期病理改变之一。组蛋白去乙酰化酶3（Histone deacetylase 3, HDAC3）是一种在神经组织内高表达的I类HDAC，有研究表明选择性抑制HDAC3可促进长期记忆形成，但是其机制尚不清楚。HDAC3在6月龄和12月龄APP/PS1小鼠海马组织表达明显上调，而在6月龄APP/PS1小鼠海马内注射HDAC3过表达病毒，能够增加Ab的沉积以及神经胶质细胞的增生，显著降低其认知和记忆功能；而靶向抑制HDAC3能够改善APP/PS1小鼠记忆和认知功能，减少b-淀粉样蛋白的沉积以及神经胶质细胞的增生，提示HDAC3是一种潜在的神经毒性的分子。机制方面的研究表明，过表达HDAC3明显下调APP/PS1小鼠海马组织突触相关基因Nur77和Homer1a的表达，而靶向抑制HDAC3能够上调Nur77和Homer1a的表达。另一方面，在HDAC3 shRNA处理的APP/PS1小鼠，抑制Nur77能够减弱HDAC3干扰所致的神经保护作用，而抑制Homer1a对此并无影响，提示抑制HDAC3的神经保护作用部分由Nur77介导。因此，我们的研究直接证明HDAC3是一种认知和记忆功能的负性调控因子，靶向抑制HDAC3可能是一种新的AD治疗策略。