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

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the 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, which 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. [Display omitted] •Postmortem and iPSC-derived FTD neurons upregulate inflammatory genes, including SPP1•FTD neurons show mitochondrial phenotypes partially rescued by SPP1 knockdown•Grafted FTD neurons show impaired cell survival and elevate reactive gliosis•Knockdown of SPP1 in FTD neurons improves engraftment and reactive gliosis Hargus and colleagues demonstrate that iPSC-derived FTD neurons and human postmortem FTD neurons show phenotypes related to mitochondrial function and neuroinflammation, including an upregulation of osteopontin. Transplanted FTD neurons show impaired survival and elicit an increased microglial response, which is partially rescued by downregulation of osteopontin in transplanted cells.