细胞外分拣蛋白病变与阿尔茨海默样神经元及突触变性相关性探讨

阿尔茨海默氏病（AD）神经病理包括阳性和阴性病变。前者为细胞外淀粉样蛋白（Ab）沉积，神经元内磷酸化tau（pTau）聚集，神经胶质炎性反应等；后者指神经元及突触丢失。学术界普遍认为神经元/突触丢失与认知功能障碍密切相关，而Ab和pTau病变与神经元/突触丢失和认识下降相关性较差。本课题组前期报道了分拣蛋白（sortilin）C-端片段在人脑发生类似Ab的细胞外沉积病变。本项目拟采用人脑材料结合动物模型，探讨分拣蛋白C片段形成与神经元及突触丢失的相关性。项目前期及预实验结果表明分拣蛋白细胞外病变与Ab及pTau病变在时空演进上存在差异；神经元分拣蛋白表达存在年龄相关性内涵体聚集，这些内涵体在神经元发生高度pTau缠结时出现溶解和丢失；动物模型实验结果显示分拣蛋白C片段在突触变性时水平上升。本项目的研究结果有望提供优化AD诊断的新工具和手段。

Neuropathological changes in Alzheimer’s disease (AD) include the so-called positive and negative pathologies. The positive neuropathologies are characterized as “added” histopathological changes, such as extracellular β-amyloid (Aβ) deposition in neuritic plaques, intraneuronal accumulation of phosphorylated tau (pTau) related to neuronal tangle formation, and neuroglial inflammatory responses. The negative neuropathologies often refer to the “lost” changes of normal neuronal constituents including neuronal somata and synapses. It is widely believed that the cognitive decline in AD is best correlated with the extent and progress of neuronal and synaptic loss, whereas Aβ and pTau pathologies are less strongly correlated to neuronal/synaptic degeneration or cognitive decline. Our group has recently identified the extracellular deposition of putative C-terminal fragments derived from sortilin, a key membrane and intracellular protein sorting protein. This grant application proposes to determine a correlative relationship between the formation of sortilin C-terminal fragments and neuronal/synaptic degeneration. Preliminary data supporting our hypothesis include: (1) The development of extracellular sortilin proteopathy does not progress fully in parallel with that of Aβ or pTau; (2) An age-related intraneuronal sortilin accumulation as granular inclusions exists in human cerebrum, which is reduced as the neurons are densely packed with pTau and appear to be degenerating in morphology; (3) Initial results from an animal (rat) model indicate the sortilin C-terminal fragments appear and increase in association with loss of synaptic proteins. We believe that the findings from this proposed project would extend novel tools for better neuropathological diagnosis of AD, and may shed new light on the development of fluid biomarker for antemortem assessment of AD risk among the elderly.