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Alteration of Microglial Metabolism and Inflammatory Profile Contributes to Neurotoxicity in Frontotemporal Dementia 3

ABSTRACT: Transcriptome profiling of microglia cells carrying a G>C mutation at the last exon (exon six) of the CHMP2B gene linked to frontotemporal dementia (dbSNP: rs63750652) and of the corresponding isogenic controls. Heterozygous and homozygous mutant cells were obtained by precision CRISPR/Cas9 genome editing. All cells were derived from human induced pluripotent stem cells (healthy donor cell line).

ORGANISM(S): Homo sapiens

PROVIDER: GSE215241 | GEO | 2023/08/10

REPOSITORIES: GEO

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Project description:Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices and an early age of onset. The disorder is highly heterogenic, comprising several genetic causes as well as a diverse phenotypic landscape of sporadic cases. Here we investigated the proteomic signatures of human brain frontal and temporal cortical lobes to identify key pathways involved in the three most frequent genetic subtypes of frontotemporal dementia. We included 38 patients with either an autosomal dominant repeat expansion in the C9ORF72 gene (n = 16), or a mutation in the GRN gene (n = 9) or the MAPT gene (n = 13), and 11 non-demented controls. Using data-independent quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for these genetic frontotemporal dementia subtypes compared to non-demented controls. Using published single cell RNA expression data for cell type enrichment we deduced the involvement of major brain cell types in driving these different protein signatures. Using gene ontology analysis, we identified distinct genetic subtype- and cell type-specific biological processes. In the GRN-mediated subtype, we observed higher protein expression related to immune processes, with a role for endothelial cells and astrocytes, and lower protein expression implicating mitochondrial dysregulation, primarily in neurons. In the MAPT-mediated subtype, we observed higher protein expression associated with dysregulation of RNA processing in multiple cell types, and lower protein expression implicating altered neuronal functioning via dysregulation of oligodendrocytes. Comparison of the MAPT-mediated frontotemporal dementia signature with one obtained from Alzheimer’s disease brains demonstrated only partial overlap in protein dysregulation, thus separating general neurodegenerative processes and highlighting the frontotemporal dementia-specific involvement of altered RNA processing and oligodendrocyte dysfunction. Taken together, our results indicate a role for different brain cell types and biological mechanisms in frontotemporal dementia, revealing both genetic subtype-specific processes, and processes shared with other neurodegenerative diseases such as Alzheimer’s disease.

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Alteration of Microglial Metabolism and Inflammatory Profile Contributes to Neurotoxicity in Frontotemporal Dementia 3

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