期刊
GLIA
卷 69, 期 3, 页码 779-791出版社
WILEY
DOI: 10.1002/glia.23929
关键词
adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP); axonal pathology; colony stimulating factor-1 receptor (CSF-1R); Csf2expression; demyelination; GM-CSF; microgliopathy
资金
- National Institutes of Health [R01NS096144, P30CA013330, R01NS091519, U54 HD090260]
Studies have shown that loss of microglia cells can lead to behavioral deficits, pathology, and increased Csf2 expression in CSF1R-deficient mice, but not neural deletion. Additionally, increased Csf2 expression was observed in callosal astrocytes, oligodendrocytes, and microglia, with increased cell densities in regions with activated microglia in CSF1R-deficient mice. These findings confirm the involvement of microglia in the pathogenesis of ALSP and provide insights for future therapeutic strategies.
Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a dementia resulting from dominantly inheritedCSF1Rinactivating mutations. TheCsf1r(+/-)mouse mimics ALSP symptoms and pathology.Csf1ris mainly expressed in microglia, but also in cortical layer V neurons that are gradually lost inCsf1r+/-mice with age. We therefore examined whether microglial or neuronalCsf1rloss caused neurodegeneration inCsf1r+/-mice. The behavioral deficits, pathologies and elevation ofCsf2expression contributing to disease, previously described in theCsf1r(+/-)ALSP mouse, were reproduced by microglial deletion (MCsf1r(het)mice), but not by neural deletion. Furthermore, increasedCsf2expression by callosal astrocytes, oligodendrocytes, and microglia was observed inCsf1r(+/-)mice and, inMCsf1r(het)mice, the densities of these three cell types were increased in supraventricular patches displaying activated microglia, an early site of disease pathology. These data confirm that ALSP is a primary microgliopathy and inform future therapeutic and experimental approaches.
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