Herpes simplex virus-1 infection alters microtubule-associated protein Tau splicing and promotes Tau pathology in neural models of Alzheimer's disease.

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.