Anti-Herpetic Tau Preserves Neurons via the cGAS-STING-TBK1 Pathway in Alzheimer’s Disease

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular amyloid beta (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with 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, NFκB 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. [Display omitted] •HSV-1 protein expression increases with Alzheimer’s disease progression.•In Alzheimer’s disease, phosphorylated tau colocalizes with HSV-1 protein.•Following HSV-1 infection, tau is phosphorylated downstream to cGAS-STING pathway.•Post-infection tau phosphorylation reduces viral protein and boosts cell viability. Hyde et al. found elevated HSV-1 protein expression in Alzheimer’s disease, with phosphorylated tau strongly colocalizing with HSV-1 proteins. They demonstrated that tau phosphorylation responds to HSV-1 via the innate immune cGAS-STING pathway, reducing HSV-1 protein expression and increasing neuronal viability, highlighting a role for tau phosphorylation in innate immunity.