基于5-HT受体亚型乙酰化修饰探讨阿尔茨海默病精神行为症状（BPSD）的发生机制与防治新途径

Behavioral and psychological symptoms of dementia (BPSD), including agitation, aggression, depression and psychosis, are common complications that occur in more than 90% of Alzheimer’s disease (AD) patients. Increased severity of BPSD is significantly accelerated with disease progression and remains the main reason for hospitalization, significantly affecting the quality life of both patients and caregivers. However, the mechanisms underlying BPSD are not known, and there is no targeted or widely effective treatment strategy available. Our previous work and preliminary data with postmortem human tissues and AD animal models suggested that changes in histone acetylation at specific serotoninergic receptor (5-HTR) subunit gene promoters are associated with the severity of BPSD in AD and concomitant antipsychotic efficacy. Given the evidence from our group and others that implicates 5-HT and its receptors in BPSD pathogenesis and antipsychotic efficacy, we propose that histone modifications at certain 5-HTR gene promoters directly contribute to the severity of BPSD in AD and that histone deacetylase (HDAC) inhibitors could mitigate these symptoms and improve antipsychotic drug efficacy. The new knowledge gained in this project could lead to the identification and future development of specific 5-HTR-associated modulators and HDAC inhibitors for the treatment of BPSD in AD patients.

约-90%阿尔茨海默病(AD)患者合并不同程度的精神行为症状(BPSD)，其机制不清、有效治疗缺乏。我们研究发现5-HT2AR基因启动子的乙酰化水平在AD+BPSD患者和AD动物模型明显降低，与抗精神病药锥体外系副作用的加重有关，去乙酰化酶抑制剂(HDACis)能够逆转这一副作用；我们还发现5-HTR亚型与年龄依赖的精神行为症状有关，且5-HT1AR与5-HT7R存在相互影响。因此我们推测5-HTR亚型基因乙酰化修饰的多样性变化能不同程度地影响BPSD各种症状的发生发展，影响抗精神病药的治疗效果。本项目拟结合人体脑标本和动物模型研究，检测5-HTR亚型基因启动子的组蛋白乙酰化修饰变化，确定其与5-HTR亚型变化和BPSD各种症状发生发展之间的对应关系；评估HDACis治疗BPSD样行为表现的潜能。为个性化应用HDACis治疗AD+BPSD的临床试验奠定基础。

阿尔茨海默病 (Alzheimer's disease，AD) 是最常见的神经退行性疾病，超过90%的AD患者会出现精神行为症状 (Behavioral and psychological symptoms of dementia，BPSD)，其临床表现包括失眠、抑郁、激惹、攻击性和精神错乱等。通过本项目我们发现5-HT6蛋白水平的变化可能是AD患者出现BPSD症状的关键因素，并且在不同时期影响着患者的行为改变。并且得出以下结论：1）5-HTRs在AD患者脑中时间与空间上呈现不同的分布特点。2）性别因素也是影响AD患者产生BPSD的重要因素之一。3）建立首个基于中国社区老年综合健康评估数据的老年认知障碍危险因素模型。