Ijezie Emmanuel C, Miller Michael J, Hardy Celine, Jarvis Ava R, Czajka Timothy F, D'Brant Lianna, Rugenstein Natasha, Waickman Adam, Murphy Eain, Butler David C
Microbiology and Immunology Department, SUNY Upstate Medical University, Syracuse, New York, USA.
Regeneron, Rensselaer, New York, USA.
Brain Pathol. 2025 Mar 26:e70006. doi: 10.1111/bpa.70006.
Herpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimer's disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection. To this end, we infected 2D and 3D human neural models with HSV-1 and monitored MAPT splicing and Tau phosphorylation. Further, we transduced SH-SY5Y neurons with HSV-1 ICP27, which alters RNA splicing, to analyze if ICP27 alone is sufficient to induce altered MAPT exon 10 splicing. We show that HSV-1 infection induces altered splicing of MAPT exon 10, increasing 4R-Tau protein levels, Tau hyperphosphorylation, and Tau oligomerization. Our experiments reveal a novel link between HSV-1 infection and the development of cytopathic phenotypes linked with AD progression.
单纯疱疹病毒1型（HSV-1）感染会改变神经元中阿尔茨海默病（AD）的关键标志物。AD的一个关键标志物是Tau蛋白的过度磷酸化，同时伴有Tau异构体水平的改变。然而，这些Tau剪接变体的失衡，特别是由于外显子10的3R到4R MAPT剪接改变所致，尚未与HSV-1感染直接相关。为此，我们用HSV-1感染2D和3D人类神经模型，并监测MAPT剪接和Tau磷酸化。此外，我们用HSV-1 ICP27转导SH-SY5Y神经元，ICP27会改变RNA剪接，以分析单独的ICP27是否足以诱导MAPT外显子10剪接改变。我们发现HSV-1感染会诱导MAPT外显子10剪接改变，增加4R-Tau蛋白水平、Tau过度磷酸化和Tau寡聚化。我们的实验揭示了HSV-1感染与AD进展相关的细胞病变表型发展之间的新联系。
