The Role Of Microglial SIRP? In PD Pahtogenesis During Aging

Parkinson's disease(PD)in a neurodegenerative disorder related to aging.The clinical manifestations are prohibitive tremor,muscle stiffness,motor retardation,balance disorder,self-discipline dysfunction with emotional and cognitive impairment.Parkinson's disease is characterized by selective loss of dopamine(DA)neurons in both Striatum and Substantia Nigra(SN),formation of Lewy body(LB)and the overactivation of microglia.The activation of microglia was found during the process of PD.It is believed that early microglial activation is beneficial to host defense,tissue repair and neuron survival.However,sustained and aberrant activation of microglia ultimately result in deleterious consequences such as DA neuron loss in PD.Microglia mediated neuroinflammation is considered as a pivotal pathophysiological contributor to several aging related neurodegenerative disorders,including Parkinson's disease(PD).However,the key molecules involved in abnormal microglia activation during aging or disease progression still need further investigation.Signal regulatory protein alpha(SIRP alpha)is a transmembrane protein that can produce bidirectional intracellular signals through binding with its ligand CD47.It is highly expressed in macrophages,which negatively regulates cellular inflammatory response and inhibits the secretion of proinflammatory factors.Notably,inhibition of SIRPa signaling in macrophage results in the dysregulation of cytokines production and phagocytosis,which is comparable to that happened in aged microgliaIn the central nervous system(CNS),microglia is an important immunocyte which SIRP alpha can also regulate its phagocytic activity.Additionally,several studies suggest an important role of CD47/SIRPa signaling in CNS disorders.However,the exact contribution of microglial SIRPa to neurodegenerative disorders has not yet been clearly elucidated.In the present study,we examined the role of SIRPa in inflammatory response of microglia during aging.We found that SIRP? signaling decreased with age while functional studies in microglia isolated from wild-type and SIRPa knock-out mice revealed inhibitory effects of SIRPa signaling in microglia activation,indicating that downregulation of SIRPa is involved in the priming of microglia during aging Furthermore,we assessed the effect of SIRP? signaling in PD pathogenesis using both cell culture and animal models.Our result suggested that microglial SIRPa deficiency enhance the inflammatory response of microglia which further accelerates the degeneration of dopaminergic neurons in LPS mice models.These results indicate that dysregulation of SIRPa signaling in microglia during aging may contribute to the pathogenesis of age related neurological disorders such as PD.