【作者】 王进；

【导师】 张辰宇；

【作者基本信息】 南京大学 ， 生物学， 2019， 博士

【摘要】 神经退行性疾病是一类以神经元丢失为特征的疾病。神经退行性疾病随着时间的推移而逐渐恶化,最终导致功能障碍。帕金森病和阿尔兹海默病是发病率最高的神经退行性疾病。目前这类疾病的发病因尚不明确且无法治愈,严重威胁人类的健康和日常生活。寻找神经退行性疾病的发病机制和治疗方法迫在眉睫。神经免疫系统与中枢神经系统的发育,正常功能,老化,损伤以及中枢神经系统的疾病息息相关。小胶质细胞作为中枢神经系统的主要神经免疫细胞对维持中枢神经系统的稳态至关重要,除此之外,小胶质细胞参与感染,损伤状态下中枢神经系统的免疫反应。在神经退行性疾病和肿瘤状态下,小胶质细胞可以被激活和/或功能紊乱,影响疾病的进程。小胶质细胞很多表面蛋白调控小胶质细胞的正常功能与激活。这些受体调控小胶质细胞的多种功能包括细胞迁移,吞噬,产生炎性介质和神经营养因子。SIRPα是一种跨膜蛋白,能够和CD47结合相互作用,产生双向的细胞信号。SIRPα在巨噬细胞等髓系细胞中高表达,通过下游的SHP-1信号通路,负向调控细胞的吞噬(don’t eat me)和炎症反应。在中枢神经系统中SIRPα主要表达于小胶质细胞和神经元。研究表明SIRPα在中枢神经系统疾病的神经免疫中发挥重要作用。但是SIRPα在小胶质细胞激活及其在神经退行性疾病中的作用尚不明确。研究SIRPα信号对小胶质细胞功能的影响,揭示其对神经退行性疾病进程的作用及其机制,对于神经退行性疾病的研究和针对该靶点开发成功的治疗法案的开发至关重要。第一部分研究的是小胶质细胞SIRPα对帕金森病疾病进程的影响。我们研究了SIRPα信号在小胶质细胞炎症反应中的作用,发现SIRPα在衰老过程中和应激下下调。功能实验发现,SIRPα下调释放了小胶质细胞炎症反应的分子开关,揭示了SIRPα在小胶质细胞激活中的抑制作用。此外,我们用细胞培养和动物模型评估了SIRPα下调帕金森病进程的影响。我们的结果表明,SIRPα缺失将导致小胶质细胞炎症反应和吞噬功能的异常,并进一步加速了MPTP和LPS帕金森小鼠模型中多巴胺神经元的丢失。在第二部分研究的是小胶质细胞SIRPα信号在阿尔兹海默症突触病理中的作用机制。我们发现,SIRPα在阿尔兹海默症的人脑组织样本中表达下降,同时在阿尔兹海默症小鼠模型中,也发现了小胶质细胞SIRPα表达的下调。细胞实验和动物实验均发现,淀粉样肽可降低小胶质细胞SIRPα的表达。SIRPα缺失加速了阿尔兹海默症小鼠的认知功能损伤,但是对淀粉样病理无明显影响。此外,SIRPα缺失增加了阿尔兹海默症病理中小胶质细胞对神经元突触的吞噬,并且减少了阿尔兹海默症中神经元突触的数量。我们的研究表明,SIRPα的缺失将增加阿尔兹海默症中小胶质细胞对神经元突触的吞噬,加重阿尔兹海默症的认知记忆功能的损伤。综合以上结果表明,老化过程中小胶质细胞SIRPα的下调可能导致小胶质细胞炎症反应和吞噬功能的异常,并最终导致年龄相关的神经系统疾病如帕金森病和阿尔兹海默症等。我们的结果揭示了小胶质细胞SIRPα在帕金森病和阿尔兹海默症中的重要作用,为帕金森病和阿尔兹海默症的治疗提供了新的靶点和思路。更多还原

【Abstract】 Neurodegenerative disease is a kind of disease characterized by loss of neurons.The diseases worsen over time,and eventually leading to neurological dysfunction.Parkinson’s disease and Alzheimer’s disease are the most common neurodegenerative diseases.So far,the pathogenesis of these diseases is not clear,and there are no effective therapies,which threaten people’s health and daily life seriously.It is urgent to find the pathogenesis and effective therapies of neurodegenerative diseases.Neuroimmune system plays an important role in the development,homeostasis,aging,injury and diseases of the central nervous system.Microglia-the main immune cells of the central nervous system,are crucial to maintain the homeostasis of the central nervous system.In addition,microglia are involved in the immune response of the central nervous system in the state of infection and injury.Microglia will be activated and/or dysregulated in the state of neurodegenerative disease and cancer,and thereby change the progression of the disease.Many surface receptros in microglia can regulate the function and cativation.These receptors regulate multiple functions of microglia including cell migration,phagocytosis,production of inflammatory mediators and neurotrophic factors.SIRPα is highly expressed in macrophages and other myeloid-lineage cells,and negatively regulates cell phagocytosis(don’t eat me)and inflammatory responses through SHP-1signaling pathway.In the central nervous system,SIRPα is mainly expressed in microglia and neurons.Researches have shown that SIRPα plays a key role in neuroimmunity in many diseases of central nervous system.However,the potential role of SIRPα in microglia activation and its role in neurodegenerative diseases is still unclear.To reveal the effects of the function on microglia and mechanism on the progression of neurodegenerative diseases,which is of great importance for the understanding and therapy of neurodegenerative diseases.The first part studies the effect of microglial SIRP on the progression of Parkinson’s disease.We studied the role of SIRP signal in the inflammatory response of microglia and found that SIRPα decreased during aging and under inflammatory stress.Functional experiments demonstrated that SIRPα down regulated the molecular switch of microglia inflammatory response,revealing the inhibitory effect of SIRPα on microglia activation.In addition,we evaluated the effect of SIRP on the downregulation of Parkinson’s disease progression using cell culture and animal models.Our results suggest that the deficiency of SIRP leads to abnormal inflammatory responses and phagocytic dysfunctions in microglia,and further accelerates the loss of dopamine neurons in MPTP and LPS Parkinson mouse models.In the second part,the mechanism of microglial SIRP signaling in the synaptic pathology of Alzheimer’s disease was studied.We found that SIRPα was down regulated in human brain tissue samples of Alzheimer’s disease,and was down regulated in microglial cells of Alzheimer’s disease mouse model.It was found that o Aβ could reduce the expression of SIRPα in microglia.SIRPα deficiency accelerated cognitive function impairment in alzheimer’s mice,but had no significant effect on amyloid pathology.In addition,the absence of SIRPα increased the phagocytosis neuronal synapses by microglia in Alzheimer’s disease and decreased the density of neuronal synapses in Alzheimer’s disease.Our study demonstrated that the loss of SIRPα will increase the phagocytosis of neuron synapses by microglia in Alzheimer’s disease and aggravate the impairment of cognitive and memory function in Alzheimer’s disease.Taken together,the above results suggest that the down-regulation of SIRPα in microglia during aging and under stress may lead to the abnormal inflammatory response and phagocytic dysfunction of microglia,and eventually lead to age-related neurological diseases such as Parkinson’s disease and Alzheimer’s disease.Our studies revealed the important role of microglia SIRPα in Parkinson’s disease and Alzheimer’s disease,and provided new targets and ideas for the therapy of Parkinson’s disease and Alzheimer’s disease.更多还原