tau介导α-synuclein调控皮层突触可塑性的作用机制研究

Dementia with Lewy body (DLB) is a common form of neurodegeneration, and there is no drug available for disease modification. The pathology of DLB is α-synuclein neuronal inclusions, accompanied by neuronal loss, which is overlapped with some other neurodegenerative diseases. Research about neurotoxicity of α-synuclein neuronal inclusions in vivo will provid a new insight into DLB. We found that synthetic α-synuclein preformed fibrils (α-Syn PFFs) led to pathologic Lewy inclusion formation within 1 month and cognitive impairment within 6 months in wild type mice, while not lead to cognitive impairment in tau knockout mice. Synaptic plasticity is closely associated with cognitive function, and it can be used as a marker for early neuronal dysfunction. We proposed to investigate the potential effect and mechanism of α-Syn PFFs on synaptic plasticity during Lewy inclusion formation and neuronal death. Specifically, we hope to use multiple techniques such as two-photon imaging, stereotaxic brain injection, animal behavioral tests, electrophysiology, to study if aggregating of α-Syn PFFs affects synaptic plasticity. We also propose to investigate the involvement of tau in α-Syn PFFs-mediated synaptic dysfunction, since tau deficiency was reported to decrease α-Syn PFFs toxicity in our previous research. In summary, the proposed study will facilitate our understanding in the pathological function of α-synuclein in neuronal circuitry, which will provide new insight into drug development for DLB.

DLB是常见的慢性神经退行性痴呆，目前尚无有效治疗。DLB主要病变为α-synuclein病理性沉积，与多种神经退行性疾病的病变存在重叠，对α-synuclein病理沉积过程中的神经毒性及机制的研究，可为DLB相关药物治疗靶点提供依据，亦可为类似疾病的研究提供新的思路。申请人前期研究显示错误折叠的α-synuclein纹状体内注射1个月后会诱导路易小体的形成，6个月后会产生明显认知及运动障碍，但是tau缺失小鼠纹状体内α-synuclein注射6个月后无明显认知及运动障碍出现。突触可塑性与认知密切相关，申请人希望进一步活体研究α-synuclein从病理沉积至认知障碍过程中对突触可塑性的影响，及tau蛋白在介导这一过程中的作用和机制。将结合双光子活体成像、脑内立体定位注射、行为学检测、脑片电生理、基因编辑等技术，多角度明确α-synuclein在神经环路中的生理作用及其机制。

神经退行性疾病路易小体痴呆（DLB）和帕金森疾病（PD）均具有α-synuclein病理性沉积扩散和认知损伤的特点，目前均无有效治疗药物。Tau缺失小鼠脑内存在多种病变，除阿尔兹海默症（AD）样神经学病变，比如突触相关蛋白减少、铁离子聚集等现象以外，还包括PD样运动损伤。突触可塑性是学习记忆的基础，我们假说α-synuclein会在早期影响神经微环路结构，tau蛋白可能会参与这一微环路调控的过程。1）进而本项目探索完成α-Syn在脑内沉积扩散对小鼠运动与认知的影响，以及探索研究了tau蛋白缺失对活体小鼠前额叶皮层长时程突触可塑性的影响。2）使用tau缺失的小鼠和果蝇进行PD相关研究发现，tau缺失会阻止MPTP诱导的小鼠行为和黑质生化损伤，阻止鱼藤酮诱导的果蝇运动、生化损伤，以及寿命降低。为明确tau蛋白在PD中的作用提供了依据。3）从新发现的细胞程序性死亡方式铁死亡角度，研究发现脂质过氧化途径关键酶ACSL4表达降低或受抑制，可缓解MPTP诱导的PD样运动和生化损伤，提示ACSL4在PD的发病与干预策略中可能发挥重要作用。上述相关研究在进行过程中，调研撰写了专著中的1章，参与发表了1篇SCI论文。