Microglial Abnormality Contributes To Cognitive Dysfunction In Down Syndrome

Down’s syndrome(DS)is the most common chromosomal abnormality disease with an incidence of about 1/750.DS patients carry an extra copy or part of chromosome 21.The clinical symptoms of DS include developmental retardation and intellectual disability.All individuals with DS develop Alzheimer’s disease-like pathology at their 40s.There are a large number of immune/inflammation related genes on chromosome 21,and DS patients display impaired immune response and systemic inflammation.Microglia represents innate immune cells in the central nervous system and plays important roles in amyloid plaque clearance,neuroinflammation,synaptic elimination and neuronal death in Alzheimer’s disease.However,the pathological role of microglia in DS brains is largely unkown.In this thesis,we evaluated the learning and memory deficits in a DS mouse model Ts65Dn using Morris water maze and new object recognition test.In addition,electrophysiological study indicates that Ts65Dn mice have impaired synaptic function.Using transmission electron microscopy,we found that synaptic density in Ts65Dn mouse hippocampus drops markedly compared to that in WT littermates.Transcriptomic analysis revealed a dysregulated transcription network of immune/inflammation-related genes in Ts65Dn mouse brains.Immunohistochemical staining also indicated abnormal proliferation and hyperactivation of microglia in Ts65Dn hippocampus,suggesting that dysregulation of microglia-mediated synapse elimination and neuroinflammation contributes to synaptic dysfunction and cognitive deficits in DS.In conclusion,we idnetified the involvement of microglia-mediated neuroinflammation in DS brains,and our study strengthens the understanding of microglial pathology in synaptic dysfunction and intellectual disability in DS,and provides a potential strategy to combat DS pathogenesis through targeting neuroinflammation.