Iyer Abhirami K, Vermunt Lisa, Mirfakhar Farzaneh S, Minaya Miguel, Acquarone Mariana, Koppisetti Rama Krishna, Renganathan Arun, You Shih-Feng, Danhash Emma P, Verbeck Anthony, Galasso Grant, Lee Scott M, Marsh Jacob, Nana Alissa L, Spina Salvatore, Seeley William W, Grinberg Lea T, Temple Sally, Teunissen Charlotte E, Sato Chihiro, Karch Celeste M
Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, VU University, Amsterdam UMC, The Netherlands.
medRxiv. 2024 May 16:2024.05.15.24307444. doi: 10.1101/2024.05.15.24307444.
Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the IVS10+16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that IVS10+16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from IVS10+16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed were recapitulated in human brain tissue and cerebrospinal fluid from mutations carriers. Together, our findings that IVS10+16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutic strategies.
神经元功能障碍作为神经退行性tau蛋白病的核心特征已得到广泛研究。然而，在各种神经退行性疾病中，有强有力的证据表明免疫细胞如小胶质细胞积极参与驱动疾病病理生理过程。在此，我们证明tau mRNA和蛋白在人类大脑的小胶质细胞以及人类诱导多能干细胞（iPSC）衍生的类小胶质细胞（iMGLs）中表达。利用携带IVS10 + 16突变的iMGLs和同基因对照，我们证明tau突变足以改变小胶质细胞的转录状态。我们发现IVS10 + 16小胶质细胞表现出细胞骨架异常、吞噬作用停滞、TREM2/TYROBP网络破坏以及代谢改变。此外，我们发现来自IVS10 + 16 iMGLs的分泌因子影响神经元健康，降低神经元中的突触密度。在突变携带者的人类脑组织和脑脊液中重现了观察到的关键特征。总之，我们的发现表明IVS10 + 16驱动小胶质细胞的细胞内在功能障碍，进而影响神经元健康，这对治疗策略的开发具有重要意义。
