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.

Human stem cell transplantation models of Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent form of dementia. It is characterized by pronounced neuronal degeneration with formation of neurofibrillary tangles and deposition of amyloid ß throughout the central nervous system. Animal models have provided important insights into the pathogenesis of AD and they have shown that different brain cell types including neurons, astrocytes and microglia have important functions in the pathogenesis of AD. However, there are difficulties in translating promising therapeutic observations in mice into clinical application in patients. Alternative models using human cells such as human induced pluripotent stem cells (iPSCs) may provide significant advantages, since they have successfully been used to model disease mechanisms in neurons and in glial cells in neurodegenerative diseases in vitro and in vivo. In this review, we summarize recent studies that describe the transplantation of human iPSC-derived neurons, astrocytes and microglial cells into the forebrain of mice to generate chimeric transplantation models of AD. We also discuss opportunities, challenges and limitations in using differentiated human iPSCs for in vivo disease modeling and their application for biomedical research.