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Microglia-specific loss of PU.1 function rescues neurodegenerative phenotypes in a mouse model of Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline of cognitive ability. An important component of AD, and other chronic neurodegenerative diseases, is generation of an innate inflammatory response within the CNS, characterized by activation of microglia, the resident immune cells of the brain. Transcription factor PU.1 has been known to play an important role in myeloid and lymphoid cell development, however its function in microglia and how it contributes to disease pathology is not well understood. Using transcriptional and chromatin state profiles during AD-like pathology in the CK-p25 mouse model of neurodegeneration, we showed that PU.1 specifically targets noncoding regions which regulate expression changes of immune response genes during AD, suggesting it may act as master regulator of microglia activation. Here, we examine the role of PU.1 in neurodegeneration by using a conditional knockout (cKO) cassette (Cx3cr1CreER+/-) to inducibly deplete PU.1 from microglia in the CK-p25 mouse model of neurodegeneration. We found that knocking out PU.1 rescues multiple neurodegenerative phenotypes. Specifically, PU.1 inhibition reduces neurodegeneration-specific increase in microglia cell number, improves neuronal survival and reverses functional synaptic plasticity deficits in the hippocampus of the CK-p25 mouse.

ORGANISM(S): Mus musculus

PROVIDER: GSE117868 | GEO | 2021/01/01

REPOSITORIES: GEO

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

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Microglia-specific loss of PU.1 function rescues neurodegenerative phenotypes in a mouse model of Alzheimer’s disease

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