美国哥伦比亚大学Gunnar Hargus研究小组发现，骨桥蛋白驱动MAPT-N279K额颞叶痴呆症患者神经元的神经炎症和细胞丢失。相关论文于2024年4月15日在线发表在《细胞—干细胞》杂志上。

研究人员将额颞叶痴呆症（FTD）患者大脑的单细胞分析与FTD的干细胞培养和移植模型相结合。研究人员发现了携带MAPT-N279K突变的FTD神经元的疾病表型，这些表型与氧化应激、氧化磷酸化和神经炎症有关，炎症相关蛋白骨桥蛋白（OPN）上调。人类FTD神经元移植到小鼠前脑后存活率降低，引起的小胶质细胞反应增加。

值得注意的是，在移植的FTD神经元中下调OPN可改善移植效果并减少小胶质细胞浸润，这表明OPN在患者神经元中具有免疫调节作用，可能是FTD的潜在治疗靶点。

据悉，FTD是一类无法治愈的早发性痴呆症，可由患者大脑中的高磷酸化tau沉积引起。然而，导致神经变性的机制在很大程度上仍然未知。

附：英文原文

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

Author: Osama Al-Dalahmah, Matti Lam, Julie J. McInvale, Wenhui Qu, Trang Nguyen, Jeong-Yeon Mun, Sam Kwon, Nkechime Ifediora, Aayushi Mahajan, Nelson Humala, Tristan Winters, Ellen Angeles, Kelly A. Jakubiak, Rebekka Kühn, Yoon A. Kim, Maria Caterina De Rosa, Claudia A. Doege, Fahad Paryani, Xena Flowers, Athanassios Dovas, Angeliki Mela, Hong Lu, Michael A. DeTure, Jean Paul Vonsattel, Zbigniew K. Wszolek, Dennis W. Dickson, Tanja Kuhlmann, Holm Zaehres, Hans R. Schler, Andrew A. Sproul, Markus D. Siegelin, Philip L. De Jager, James E. Goldman, Vilas Menon, Peter Canoll, Gunnar Hargus

Issue&Volume: 2024-04-15

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.

DOI: 10.1016/j.stem.2024.03.013

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00094-8