Roy Ethan R, Wang Qiang, Huang Kexin, Li Sanming, Fan Yuanyuan, Escobar Estrella, Atkins Constance L, Huang Shuning, Herrera Juan J, Li Wenbo, Pridans Clare, Zhou Xiaobo, Ju Cynthia, Cao Wei
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
University of Texas Health Science Center at Houston, 77030, Houston, TX, USA.
Sci Rep. 2025 Jul 29;15(1):27664. doi: 10.1038/s41598-025-12869-9.
The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimer's disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the mouse brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by cellular stress in neurons and reactive gliosis in multiple brain regions. Notably, the lifelong absence of microglia significantly and differentially influenced the extent of neurodegeneration in the hippocampus and thalamus. Therefore, our study established an AD-relevant tauopathy mouse model, elucidated both neuron-intrinsic and neuron-extrinsic responses, and highlighted critical and complex roles of microglia in modulating tau-driven neurodegeneration.
异常的、未发生突变的tau蛋白的积累是阿尔茨海默病（AD）的关键病理标志。尽管其与疾病进展密切相关，但tau蛋白驱动大脑神经退行性变的机制仍知之甚少。在此，我们在小鼠全脑的神经元中选择性表达未发生突变或发生突变的人类微管相关蛋白tau（hMAPT），并观察到海马体中的神经退行性变，尤其是与未发生突变的人类tau蛋白相关的神经退行性变。单核RNA测序证实野生型tau蛋白导致海马体兴奋性神经元选择性缺失，并揭示了受影响群体中神经退行性变相关通路的上调。磷酸化tau蛋白的积累伴随着神经元中的细胞应激以及多个脑区的反应性胶质增生。值得注意的是，小胶质细胞的终身缺失对海马体和丘脑神经退行性变的程度有显著且不同的影响。因此，我们的研究建立了一个与AD相关的tau蛋白病小鼠模型，阐明了神经元内在和外在反应，并突出了小胶质细胞在调节tau蛋白驱动的神经退行性变中的关键和复杂作用。
