Project description:Changes in microglial form and function contribute to age-related cognitive impairment. Developing methods to target microglia is critical to understand and prevent the adverse effects of aging. Using a specific colony-stimulating factor 1 receptor (CSF1R) inhibitor, our lab has shown that the majority of microglia can be eliminated from the CNS (Elmore et al., 2014). Withdrawal of the CSF1R inhibitor, stimulates brain-wide repopulation with new cells, that express microglial markers (Elmore et al., 2014; Elmore et al., 2015). The impact of these newly repopulated cells on the aged brain has not been explored, but will provide useful insight into the role of microglia in aging. In addition, the therapeutic potential of replacing “primed” or “senescent” microglia in the aged brain with new cells is of great interest. Therefore, our goal was to fully characterize the gene expression profiles of the aged control vs. aged repopulated brains in comparison to young controls.
Project description:Cx3cr1CreER-Eyfp/wt mice contain a subset of microglia lacking Cre and EYFP expression. These microglial escape Cre-mediated recombination and gain a repopulation advantage following Cre-driven DTA-mediated microglial depletion.
Project description:Over the past decade, genetic evidence has demonstrated that microglial dysregulation is likely to play a central role in the development of Alzheimer's disease (AD). As resident immune cells in the brain, microglia become dystrophic and senescent during the chronic progression of AD. To explore whether replenishing the brain with new microglia is beneficial to AD, we employed a CSF1R inhibitor PLX3397 to deplete microglia and induce repopulation after the inhibitor withdrawal in 5xFAD transgenic mice. We observed that microglial repopulation ameliorates AD-associated cognitive deficits, accompanied by elevation of synaptic proteins and hippocampal long-term potentiation (LTP). In addition, microglial morphology is restored after microglial self-renewal, and amyloid pathology is reduced with long-term repopulation but not short-term. Transcriptome analysis showed that repopulating microglia in 5xFAD mice recovers a gene expression profile that is highly similar to microglia from WT mice. Notably, the neurotrophic signaling pathway and hippocampal neurogenesis dysregulated in the AD brain are restored after microglial replenishment. At last, we confirmed that microglial repopulation rescues brain-derived neurotrophic factor (BDNF) expression to contribute to synaptic plasticity. Together, we conclude that microglial self-renewal benefits AD brain by restoring the BDNF neurotrophic signaling pathway. Thus, the proper replenishment of microglia may be an effective and novel therapeutic strategy for ameliorating cognition impairment in AD.
Project description:To determine the transcriptomic changes underlying the MIA microglia phenotype and their reversal by PLX, we performed RNA-sequencing of magnetic CD11B beads-isolated microglia from the whole brain in Saline and MIA male and female offspring at E17, P7, P20, and P60, as well as from MG-REP male and female offspring at P60. Microglial transcriptome reveals novel MIA and repopulation modules and overlap of MIA microglial genes with ASD gene network. 14,225 microglial genes from RNA-seq data revealed distinct transcriptional signatures of immature microglia (IM module, 4681 transcripts, enriched in E17 and P7 Saline), MIA immature microglia (MIA-IM module, 2816 transcripts, enriched in E17 and P7 MIA), Juvenile microglia (JM module, 2318 transcripts, enriched in P20 Saline and MIA), Adult microglia (AM module, 3276 transcripts, enriched in P60 Saline + CTRL, P60 MIA + CTRL and P60 MIA + MG-REP), and repopulated adult microglia (REP-AM module, 1,134 transcripts, enriched in P60 Saline + MG-REP)
Project description:This dataset allows for the exploration of microglial function on gene expression in wild-type and the 5xFAD mouse model of Alzheimer's disease, across multiple brain regions. Mice were treated with the selective CSF1R inhibitor PLX5622, which eliminates >95% of microglia in less than 5 days, from 1.5 to 7 months of age. Thus, these data allow the exploration of the effects, and specificity, of 6 months microglial depletion, in both wild-type and 5xFAD mice.