DAPK1通路参与AD早期认知功能损害的机制研究

Alzheimer's Disease (AD) is the most common neurodegenerative disease that seriously affects the health of the elderly population, and AD-related neuropathological changes in the brain have already occurred before the onset of clinical symptoms of AD. Based on the classical beta-amyloid (Aβ) hypothesis, studies have demonstrated that the oligomeric form Aβ has greater neurotoxicity and pathogenicity than monomeric form Aβ and fibrous form Aβ, and Aβ oligomers play crucial roles in the pathogenesis of AD and are closely related to neurodegeneration and cognitive impairment at the early stage of AD. Death-associated protein kinase 1 (DAPK1) signaling plays important roles in various neuronal damage and learning and memory process. Studies have confirmed that DAPK1 gene polymorphisms are correlated with the risk of AD and is also involved in the neurodegenerative process of AD. However, the mechanism of DAPK1 signaling involved in neuronal damage and cognitive impairment at the early stage of AD has not been studied yet. On the basis of our previous results that DAPK1 signaling in the brain of Aβ oligomers animal model with cognitive impairment was remarkably activated and DAPK1 level was immediately up-regulated after Aβ oligomers treatment in cell culture experiment, this project will further explore and verify the neurobiological mechanism of DAPK1 signaling involved in the neuronal damage and cognitive impairment at the early stage of AD through cell culture and animal studies. This project intends to provide new insights for the early pathogenesis of AD and novel target for the early intervention and treatment in AD.

阿尔兹海默病(Alzheimer’s Disease, AD)是严重危害老年人群健康的神经退行性疾病，AD相关神经病理改变在临床症状出现前已发生。研究证实寡聚体形式淀粉样蛋白(β-amyloid, Aβ) 在AD早期病理变化中具有更强的神经毒性和致病作用。死亡相关蛋白激酶1(Death-associated protein kinase 1, DAPK1)参与脑内多种神经损伤和学习记忆过程，与AD发病风险和AD相关退行性病理改变密切相关，但DAPK1通路在AD早期阶段的神经损伤和认知损害过程中的作用机制尚不明确。在我们前期发现认知功能下降的Aβ寡聚体模型动物脑内DAPK1通路显著激活和细胞水平上Aβ寡聚体可导致DAPK1快速上调基础上，本项目拟从细胞和动物水平上深入研究和验证DAPK1通路参与AD早期阶段神经损伤和认知功能损害的神经生物学机制，以期为AD早期干预和治疗提供新靶点。

阿尔茨海默病(Alzheimer’s disease，AD)是老年人群中最常见的痴呆症。近年来，绝大多数基于AD经典病理标志Aβ和tau的临床药物试验的失败表明AD的病理机制十分复杂，且病程进展中伴随多种异常生物学功能的动态改变。本项目主要基于团队前期临床队列基础和动物模型研究，发现了DAPK1，Wnt2b和IGF-1可能是AD潜在的重要病理蛋白靶点和关键致病机制。我们发现DAPK1在AD早期病理阶段显著激活，并通过增加与NMDA受体GluN2B亚基结合和磷酸化，引起神经细胞内钙水平增加和神经损伤，同时我们发现AD患者外周血DAPK1水平显著高于认知正常对照，同时与认知功能负性相关。Wnt2b是一种Wnt家族成员，我们首次发现AD患者外周血中Wnt2b水平较认知正常组显著减低，且与认知功能正性相关，进一步研究发现Wnt2b与AD线粒体损伤关系密切，内源性增加神经细胞WNT2B表达和动物模型和外源性给予Wnt2b重组蛋白可以显著改善AD线粒体功能和形态学异常，并基于Wnt2b的关键病理作用和治疗潜力申请了一项国家发明专利。我们在临床荟萃分析中发现IGF-1在AD诊断中具有重要价值，AD患者的外周血和脑脊液中IGF-1水平显著低于认知正常组，MCI患者外周血中IGF-1较认知正常组有降低趋势。综合上述三种病理蛋白和机制的研究，为我们更好理解AD病理发生发展机制提供了新的角度，同时也为AD的干预治疗提供了病理靶点。