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Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

ABSTRACT: Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, that we further characterized by single nucleus RNA-sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230450 | GEO | 2024/04/15

REPOSITORIES: GEO

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Project description:Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein tau. Due to limited availability of neural cells from patients` brains, however, the underlying mechanisms of neurodegeneration in FTD are still only poorly understood. Here, we derived induced pluripotent stem (iPS) cells from individuals with FTD-associated MAPT mutations and differentiated them into neurons for mechanistic studies. Patient-derived neurons demonstrated pronounced tau pathology with increased fragmentation and AT8-immunoreactivity, disturbed neurite extension and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD-neurons showed activation of the unfolded protein response and presented with distinct, disease-associated gene expression profiles in a whole-genome transcriptome analysis. These findings indicate distinct, early neurodegenerative changes in FTD caused by mutant tau and highlight the unique opportunity to use patient-specific iPS cells to identify potential targets for drug screening purposes and therapeutic intervention. RNA samples for microarray analysis were prepared using RNeasy columns (Qiagen, Germany) with on-column DNA digestion. 300 ng of total RNA per sample were used as the input in the linear amplification protocol (Ambion), which involved the synthesis of T7-linked double-stranded cDNAs and 12hrs of in vitro transcription incorporating biotin-labeled nucleotides. Purified and labeled cRNA was then hybridized for 18 hrs onto HumanHT-12 v4 expression BeadChips (Illumina, USA) following the manufacturer’s instructions. After the recommended washing, the chips were stained with streptavidin-Cy3 (GE Healthcare) and scanned using the iScan reader (Illumina) and the accompanying software. The samples were exclusively hybridized as biological replicates. The bead intensities were mapped to the corresponding gene information using BeadStudio 3.2 (Illumina) and background correction was performed using the Affymetrix Robust Multi-array Analysis (RMA) background correction model (Irizarry et al., 2003). Variance stabilization was performed using the log2 scaling, and gene expression normalization was calculated with the quantile method implemented in the lumi package of R-Bioconductor. Data post-processing and graphics were performed with in-house developed functions in MATLAB. Hierarchical clusters of genes and samples were performed with the one minus the sample correlation metric and the Unweighted Pair-Group Method using Average (UPGMA) linkage method.

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Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

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