Shultz Andrew, Vincze Anna, Yau Todd T, Poirier Emma L, Rauch Jennifer N
Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, MA, USA.
Molecular and Cellular Biology Graduate Program, University of Massachusetts, Amherst, Amherst, MA, USA.
bioRxiv. 2025 Jun 25:2025.06.23.661190. doi: 10.1101/2025.06.23.661190.
Microglia are the tissue resident macrophages of the brain and their contribution to tau pathology progression remains to be fully understood. In this study, we developed a quantitative platform to elucidate the endo-lysosomal regulation of tau within human induced pluripotent stem cell (iPSC)-derived microglia. We show that iPSC-derived microglia internalize monomeric and fibrillar tau through different cellular mechanisms and with different degradation kinetics. Acute inflammatory activation of microglia alters tau endocytosis, but surprisingly does not impact lysosomal clearance. These results highlight the importance of the microglial endo-lysosome system as a regulator of tau pathology that is decoupled from acute microglial activation.
小胶质细胞是脑内组织驻留巨噬细胞，它们对tau蛋白病理进展的作用仍有待充分了解。在本研究中，我们开发了一个定量平台，以阐明人诱导多能干细胞（iPSC）衍生的小胶质细胞内tau蛋白的内吞溶酶体调节机制。我们发现，iPSC衍生的小胶质细胞通过不同的细胞机制、以不同的降解动力学内化单体和纤维状tau蛋白。小胶质细胞的急性炎症激活会改变tau蛋白的内吞作用，但令人惊讶的是，并不影响溶酶体清除。这些结果凸显了小胶质细胞内吞溶酶体系统作为tau蛋白病理调节因子的重要性，该调节与小胶质细胞的急性激活无关。
