Hyde Vanesa R, Zhou Chaoming, Fernandez Juan R, Chatterjee Krishnashis, Ramakrishna Pururav, Lin Amanda, Fisher Gregory W, Çeliker Orhan Tunç, Caldwell Jill, Bender Omer, Sauer Peter Joseph, Lugo-Martinez Jose, Bar Daniel Z, D'Aiuto Leonardo, Shemesh Or A
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Cell Rep. 2025 Jan 28;44(1):115109. doi: 10.1016/j.celrep.2024.115109. Epub 2025 Jan 2.
Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus protein ICP27 increases with AD severity and strongly colocalizes with p-tau but not with Aβ. Modeling in human brain organoids shows that HSV-1 infection elevates tau phosphorylation. Notably, p-tau reduces ICP27 expression and markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into the cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB and IRF-3, which colocalizes with ICP27 and p-tau in AD. Furthermore, experimental activation of STING enhances tau phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest that tau phosphorylation acts as an innate immune response in AD, driven by cGAS-STING.
阿尔茨海默病（AD）的诊断依赖于细胞外β淀粉样蛋白（Aβ）和细胞内过度磷酸化的tau蛋白（p-tau）的存在。新出现的证据表明，AD病理与感染因子之间存在潜在联系，单纯疱疹病毒1型（HSV-1）是主要候选者。我们利用宏基因组学、质谱分析、蛋白质免疫印迹和去拥挤扩展病理学进行的研究，在人脑样本中检测到了与HSV-1相关的蛋白质。疱疹病毒蛋白ICP27的表达随AD严重程度增加而升高，且与p-tau强烈共定位，但与Aβ不共定位。在人脑类器官中的建模显示，HSV-1感染会提高tau蛋白的磷酸化水平。值得注意的是，p-tau会降低ICP27的表达，并使感染后神经元死亡从64%显著降至7%。该建模促使对cGAS-STING-TBK1信号通路产物、核因子（NF）-κB和IRF-3进行研究，它们在AD中与ICP27和p-tau共定位。此外，STING的实验性激活会增强tau蛋白的磷酸化，而TBK1的抑制则可防止这种情况发生。这些发现共同表明，tau蛋白磷酸化在AD中作为一种由cGAS-STING驱动的先天性免疫反应发挥作用。
