Year: 2020
Type: article
Abstract: Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,990
Awards: Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology, Whole genome sequencing consortium on Frontotemporal dementia with underlying TDP-43 pathology, Identification of exosome signature in serum from ALS patients, Integrative translational discovery of vascular risk factors in aging and dementia, Impact of coding and non-coding variation in progressive supranuclear palsy, Identification of MicroRNA and Proteomics in immune cells and plasma in ALS, Einstein Aging Study, Impact of ApoE2 on aging-related conditions, Clinicopathologic and Neuroimaging Differences in Alzheimer's Disease Variants, The role of aging-associated microRNAs in Alzheimer's disease, Pathobiology of Neurodegeneration in C9ORF72 repeat expansion, Microglial mechanisms of postoperative CNS inflammation and cognitive decline, Role of microRNA-33 in Alzheimer's disease, Role of LDLR in regulating metabolism of Apolipoprotein E and Amyloid-beta, Identifying genes and Pathways that impact Tau Toxicity in FTD, Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS), Alzheimer's Disease Research Center, microRNA-758-3p in cognition and Alzheimer's Disease, Role of Microglia in Retinitis Pigementosa, Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 Proteinopathies, Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimerâs disease, Targeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple Sclerosis, Alzheimer's Disease Research Center, Mayo Alzheimer's Disease Research Center, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W3027370519