阿尔茨海默病风险基因SERPINF1的鉴定与作用机制研究

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the most common form of dementia. Immune response, esp. inflammation, plays an important role in the pathogenesis of AD. We found that Complement Factor H (CFH) gene, an anti-inflammation regulator, act as an AD risk gene (Zhang et al. Neuropsychopharmacology 2016), adding more evidence for the involvement of immune response in AD. Recently, we found that SERPINF1 gene, through integrating whole genome methylation screening and expression profiling data, is down-regulated in AD brain tissues, and act as a hub node in the functional network consisted by key AD-risk immune genes such as CFH and APOE. We also found genetic variations within this gene confer to AD risk. The mechanism of the involvement of SERPINF1, CFH and their related interacting immune genes in AD needs further characterization. In this project, we planned to validate the expression change, explore the regulation of expression alteration, and investigate the immune network in AD cellular and animal models and patients. The identification and characterization of the new risk gene SERPINF1 in AD will contribute to the understanding of genetic and pathological basis of AD, and provide support to the prediction, diagnosis, and treatment of the disease.

阿尔茨海默病（Alzheimer’s disease，AD）是最典型的神经退行性疾病与最常见的痴呆。免疫炎症反应在AD病理过程中发挥重要作用。我们前期发现免疫基因CFH影响AD遗传风险与免疫反应（Zhang et al. Neuropsychopharmacology 2016）。最近，通过整合AD脑组织全基因组甲基化扫描与表达谱数据，我们筛选到SERPINF1基因受甲基化调控而发生显著的表达改变，且其遗传变异影响基因表达与AD遗传风险；并发现SERPINF1与CFH及其他AD重要基因形成免疫作用网络。本项目拟从细胞、小鼠模型和AD病人等层面，进一步分析AD发生过程中SERPINF1的表达模式与其表达调控的机制，探索SERPINF1与CFH及其相关免疫网络在AD神经细胞免疫反应等病理过程中的作用机制。研究结果可为SERPINF1及其相关通路作为AD潜在诊断与治疗靶点提供理论基础。

阿尔茨海默病（Alzheimer’s disease，AD）是老年高发的、典型的神经退行性疾病，导致的社会经济负担沉重。目前尚无有效药物或干预手段能延缓其疾病进程。深入全面的分子机制解析将为有效的药物靶点开发提供基础数据。我们整合AD脑组织全基因组甲基化扫描与表达谱数据，筛选到SERPINF1基因受甲基化调控而发生显著的表达改变；进一步研究发现，1）该基因上存在AD易感位点，这些AD易感位点影响了SERPINF1甲基化水平与基因表达水平；2）在我国高遗传力AD 病例中存在的SERPINF1稀有错义突变；3）细胞实验表明，SERPINF1的表达改变或突变，通过CDK5通路，促进AD分子病理改变；4）动物水平在体实验发现，小鼠海马敲降或过表达SERPINF1稀有错义突变，使小鼠记忆能力受损；5）过表达SERPINF1野生型蛋白或外源SERPINF1蛋白处理，可以发挥记忆与神经元保护作用。我们的研究结果为SERPINF1及其相关通路作为AD潜在诊断与治疗靶点提供理论基础。本项目执行期间，发表与项目相关且标注资助的SCI论文3篇，参加人员3人获得职称晋升，项目相关博士毕业生1名，硕士毕业生2名。