Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons
Osama Al‐Dalahmah, Matti Lam, Julie J. McInvale, Wenhui Qu, Trang Nguyen, Jeong-Yeon Mun, Sam Hyun Kwon, Nkechime Ifediora, Aayushi Mahajan, Nelson Humala, Tristan Winters, Ellen Angeles, Kelly Jakubiak, Rebekka Kuhn, Yoon A. Kim, Maria Caterina De Rosa, Claudia A. Doege, Fahad Paryani, Xena Flowers, Athanassios Dovas, Angeliki Mela, Hong Lü, Michael DeTure, Jean Paul Vonsattel, Zbigniew K. Wszołek, Dennis W. Dickson, Tanja Kuhlmann, Holm Zaehres, Hans R. Schöler, Andrew A. Sproul, Markus D. Siegelin, Philip L. De Jager, James E. Goldman, Vilas Menon, Peter Canoll, Gunnar Hargus
Abstract
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.