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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

ABSTRACT: Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

PROVIDER: PRJNA554106 | ENA |

REPOSITORIES: ENA

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Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model

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.

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Therapeutic potential of human microglial transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant primary microgliopathy caused by mutations in colony-stimulating factor 1 receptor (CSF1R). CSF1R signaling is necessary for microglial differentiation and survival. As a result, ALSP patient brains have fewer microglia and exhibit an array of neuropathologies including axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcification. To explore the therapeutic potential of transplanting healthy human microglia, we generated ‘hFIRE’ mice, a xenotolerant mouse model of ALSP that lacks murine microglia. Remarkably, transplantation of induced pluripotent stem cell (iPSC)-derived microglial progenitors enabled rapid CNS-wide microglial engraftment, restoring a homeostatic microglial gene signature and preventing diverse ALSP-related neuropathologies. To further examine a potential autologous approach, ALSP-patient derived iPSCs were CRISPR-corrected, rescuing mutation-induced deficits in microglial proliferation, enabling brain-wide microglial engraftment, and reducing pre-existing spheroid, astroglial, and calcification pathologies within just 6 weeks. Together with the accompanying study by Munro and Colleagues, these results demonstrate the utility of FIRE mice to model diverse ALSP neuropathologies and provide initial evidence that iPSC-microglia could be further developed as a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

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single-cell RNA-seq profile of adult microglia under acute Csf1r inhibition and early repopulation

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single-cell RNA-seq profile of microglia under acute Csf1r inhibition and early repopulation in adult brain

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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.

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Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer’s disease mouse model.

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Microglial-expressed Apoe does not modulate plaque pathogenesis

Project description:This dataset allows for the exploration of the effect of microglial-expressed Apoe knockout in a 5xFAD Alzheimer's Disease model.

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Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

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