Microglial reduction of colony stimulating factor-1 receptor expression is sufficient to confer adult onset leukodystrophy

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.