A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes

Colombo, Gloria; Cubero, Ryan John; Kanari, Lida; Venturino, Alessandro; Schulz, Rouven; Scolamiero, Martina; Agerberg, Jens; Mathys, Hansruedi; Tsai, Li‐Huei; Chachólski, Wojciech; Hess, Kathryn; Siegert, Sandra

doi:10.1038/s41593-022-01167-6

Cited by 45 publications

(44 citation statements)

References 78 publications

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“…Sex-specific differences exist in mouse microglial morphology, function, gene expression, and response to tauopathy, and the differences increase with age 63 – 66 . Our data identify a sex-dependent effect on therapeutic exposure and efficacy of CSF1R inhibition in Tg2541 mice.…”

Section: Discussionmentioning

confidence: 99%

CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model

et al. 2023

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Microglia are central to pathogenesis in many neurological conditions. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we show that CSF1R inhibitors given by multiple dosing paradigms in the Tg2541 tauopathy mouse model cause a sex-independent reduction in pathogenic tau and reversion of non-microglial gene expression patterns toward a normal wild type signature. Despite greater drug exposure in male mice, only female mice have functional rescue and extended survival. A dose-dependent upregulation of immediate early genes and neurotransmitter dysregulation are observed in the brains of male mice only, indicating that excitotoxicity may preclude functional benefits. Drug-resilient microglia in male mice exhibit morphological and gene expression patterns consistent with increased neuroinflammatory signaling, suggesting a mechanistic basis for sex-specific excitotoxicity. Complete microglial ablation is neither required nor desirable for neuroprotection and therapeutics targeting microglia must consider sex-dependent effects.

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Section: Discussionmentioning

confidence: 99%

CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model

et al. 2023

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“…In agreement with the observed reduction in phagocytic function, we observed that the loss of CYFIP1 expression in these iMGs results in increased ramification consistent with a less activated state. (67,73,74) Microglial motility into and within the CNS is also essential to proper neurodevelopment and maintenance functions. (75) These cells must first properly migrate from the primitive yolk sac to populate the developing brain during early development to become permanently brain-resident throughout life.…”

Section: Discussionmentioning

confidence: 99%

“…(72) Thus, various microglial morphotypes in these different contexts suggest a form-function relationship in which morphology and expression of various markers can be used as a proxy for functional state. (73, 74) CYFIP1 protein has been demonstrated to directly interact with the Wiskott-Aldrich syndrome protein member 1 (WAVE1) regulating dendritic cytoskeletal modulation of ARP2/3-mediated actin branching. (40-42) Our morphological characterization in CYFIP1 loss-of-function iPSC-derived microglia implicates a direct role in the cytoskeletal processes involved in proper function.…”

Section: Discussionmentioning

confidence: 99%

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Loss of function in the autism and schizophrenia-associated geneCYFIP1in human microglia supports a role in synaptic pruning

Sheridan

Horng

Yeh

et al. 2022

Preprint

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Background: The CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood. Methods: We generated multiple CRISPR knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human iPSC-derived neuronal cultures as an in vitro model of synaptic pruning. We repeated these analyses in human iPSC-derived microglia, and characterized microglial development and function through morphology and motility. Results: CYFIP1 knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with statistically significant decrease in synaptic vesicle phagocytosis in microglia models derived from both PBMCs and iPSCs (p<0.0001). Morphology was also shifted toward a more ramified profile (p<0.0001), and motility was significantly reduced (p<0.0001). However, iPSC-CYFIP1 knockout lines retained the ability to differentiate to functional microglia. Conclusion: The changes in microglial phenotype and function from loss of CYFIP1 may contribute to pruning abnormalities observed in CYFIP1-associated neurodevelopmental disorders. Investigating risk genes in a range of CNS cell types may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders.

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“…Sex-specific differences exist in mouse microglial morphology, function, gene expression, and response to tauopathy, and the differences increase with age [63][64][65][66] . Our data identify a sexdependent effect on therapeutic exposure and efficacy of CSF1R inhibition in Tg2541 mice.…”

Section: Discussionmentioning

confidence: 99%

CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice

Yuan

et al. 2021

Preprint

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Microglia are a fundamental component of pathogenesis in many neurological conditions and have specialized functions that vary by disease stage or specific pathology. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we evaluated CSF1R inhibitors in tauopathy mice using multiple dosing schemes, drug analogs, and longitudinal measurements in the brain and plasma. In both spontaneous disease and in tau fibril inoculation models, we found a region-dependent reduction in insoluble phosphorylated tau and replication-competent tau in mice treated with CSF1R inhibitors. Surprisingly, despite greater drug exposure and microglial depletion in male mice, we observed a rescue of aberrant behavior, reduced plasma neurofilament light chain, and extended survival in female mice only. Gene expression patterns in CSF1R inhibitor-treated tauopathy mice reverted toward a normal wildtype signature, and in vivo imaging revealed suppressed astrogliosis. However, we observed drug dose-dependent upregulation of immediate early genes in male mice only, indicating excitotoxicity, which may have masked functional benefits. Drug-resilient microglia in tauopathy mice exhibited a ramified morphology similar to wildtype microglia but with greater territory occupied per cell, and their transcriptome was neither disease-associated nor homeostatic, suggesting a unique microglial subtype. Our data argue that complete or continuous microglial ablation is neither required nor desired for neuroprotection, and that selective depletion of detrimental, tauopathy-activated microglia may be achieved by precise timing and dosing of CSF1R inhibitors. Importantly, therapeutics targeting microglia must consider sex-dependent effects on functional outcomes when weighing their translational potential for neurological disease.

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A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes

Cited by 45 publications

References 78 publications

CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model

CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model

Loss of function in the autism and schizophrenia-associated geneCYFIP1in human microglia supports a role in synaptic pruning

CSF1R inhibitor levels determine sex-specific phenotype of resilient microglia and neurofunctional rescue leading to extended survival in tauopathy mice

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