ACAA1参与阿尔茨海默病发生发展的分子机制

Alzheimer's disease (AD) is the main type of dementia and the most common neurodegenerative disease. The development of AD is affected by many factors. Old age, hypertension, hyperlipidemia, brain damage, and low education level are all risk factors for AD. At the same time, the development of AD is affected by genetic factors, and its heritability is as high as 79%. Due to the complex etiology of AD, there is very limited therapeutic drug and approach for curing AD, and the risk for developing a new drug for AD is very high. Along with the ageing of the Chinese population, we have a heavy social and economic burden due to AD. Therefore, the research on the pathogenesis of AD is an urgent task. We and colleagues collected a familial AD pedigree from Guizhou Province recently. We conducted a whole-genome analysis for the probands and related family members and found that all AD patients had a missense ACAA1 variant (p.N299S). Preliminary functional characterization showed that ACAA1 p.N299S can damage the lysosomal system and cellular biochemical activity, and cause synaptic dysfunction. In this project, we aim to carry out in-depth study of ACAA1 and its mutation at the genetic, cellular and animal model levels. We will screen the ACAA1 p.N299S in Han Chinese with AD. By using gene overexpression and knockdown of ACAA1 and its mutation, we will study the effects of ACAA1 and its mutation on neuronal function. We will employ AD mouse model to study the effect of ACAA1 and its mutation on neuronal synaptic plasticity, AD pathological processes and cognitive impairment, to clarify its role in the pathogenesis of AD. The findings will confirm ACAA1 as a novel risk gene for AD and provide first-handed information for treating this gene as a potential target for early genetic diagnosis and intervention of AD.

阿尔茨海默病（AD）是痴呆的主要类型，也是最常见的神经退行性疾病。AD发生发展受高龄、高血压、高血脂、脑损伤、教育程度低等影响，同时受遗传因素影响，遗传力高达79%。目前AD的治疗药物极其有限，失败风险很高。随着人口老龄化的加剧，AD带来的社会经济负担日渐沉重。前期申请人与合作者收集了一个贵州的AD家系，进行全基因组分析后发现，该家系中AD患者携带有一个ACAA1的稀有变异（p.N299S），初步研究显示该突变可破坏神经细胞的溶酶体系统，产生生化异常和突触功能紊乱。本项目拟从遗传、细胞、动物模型等多个角度，开展系统研究；通过基因过表达及敲降，研究ACAA1及其突变对神经细胞功能的影响；利用AD小鼠模型，研究ACAA1及其突变在突触可塑性、AD病理进程及认知障碍行为中的作用，阐明其参与AD发病的机制。研究结果有望为AD的早期遗传诊断提供依据，并为以ACAA1为靶点的药物研发奠定基础。

阿尔茨海默病(Alzheimer's disease, AD)是严重危害老年群体健康的主要疾病之一。AD的特点是进行性突触功能障碍、神经元死亡和脑萎缩，脑组织中出现淀粉样β（Aβ）斑块沉积和高磷酸化tau神经纤维缠结积累，这些都导致了认知功能的丧失。众所周知的AD致病基因包括APP、PSEN1和PSEN2的致病突变损害了多种途径，包括蛋白质加工、轴突运输和代谢稳态。在本项目研究中，我们通过全基因组测序在一个汉族AD家族中发现了乙酰-CoA酰转移酶1（ACAA1）基因的错义变异rs117916664（c.896T>C，p.Asn299Ser[p.N299S]），并在一个独立队列中验证了它与早发家族性AD的关联。进一步的，通过体外和体内系统研究，我们发现ACAA1 p.N299S通过扰乱其酶活性，损害溶酶体功能，加剧Aβ病理和神经元损失，最终在小鼠模型中引起认知障碍，从而在AD发病发病过程中起着至关重要的作用。我们的这项研究揭示了过氧化物酶体介导的溶酶体功能障碍在AD发病机制中的重要作用。目前项目任务书内的研究工作已经全部完成，对ACAA1参与AD的具体机制进行了系统解析。研究结果有望为AD的早期遗传诊断提供依据，并为以ACAA1为靶点的药物研发奠定基础。项目执行期内培养毕业硕士研究生1名，发表SCI论文9篇。团队成员1人完成职称晋升，1人入选中国科学院青年创新促进会会员，1人入选云南省科协青年人才托举工程，1人入选云南省“兴滇英才支持计划”青年人才，并获得云南省优秀青年科学基金的资助。通过本项目有力地带动了人才培养和队伍建设。