A recent longitudinal study confirms a powerful correlation between neurodegeneration, including Alzheimer’s disease (AD), and a history of viral infections. The strongest correlation suggests that AD is caused by viral encephalitis. Herpes simplex virus 1 (HSV-1), a common neurotropic virus and a known cause of encephalitis, has repeatedly been shown to be connected to AD, suggesting a potential relationship between the disease and viral infections.
Dr. Martin Tyers, the study’s lead researcher, explained that tau, a brain protein typically associated with Alzheimer’s disease, initially acts as a protective agent, helping the brain resist viral attacks. However, its protective role diminishes over time, becoming harmful. The findings could yield new treatments against infections and the brain’s immune response.
“Our work challenges the notion that tau is always harmful and challenges the notion that these astrocytes [minimally pathogenic brain cells trapped within bulbar lesions] come in to dissolve the wormhole,” said senior author Or Shemesh, Ph.D., assistant professor of ophthalmology at Pitt.
In a large Taiwanese study, HSV 1 infection plus not receiving treatment increased the risk of dementia by 2.56 fold, however, HSV 1 infection plus treatment with anti-herpes medications reduced the additional risk. A VZV (varicella-zoster virus) vaccine lowers the incidence of neurological disease and dementia, but an HSV-1 (herpes simplex virus 1) vaccine is under development.
In Alzheimer’s brain samples, the scientists identified HSV-1-related proteins, and viral proteins co-localized with high levels of phosphorylated tau tangles, one hallmark of Alzheimer’s disease pathogenesis, in brain regions most vulnerable to Alzheimer’s across disease stages. Although HSV-1 is detectable in serum and cerebrospinal fluid, it is rarely found in brain samples, creating a significant challenge in understanding its role in AD.
If HSV-1 is active in AD, it doesn’t typically lead to the production of viral particles. However, the virus may persist without causing viral encephalitis through the expression of HSV-1 proteins. Importantly, HSV-1 DNA has been associated experimentally with AD pathologies. HSV-1-induced Aβ production is proposed to have antimicrobial properties, and studies suggest that HSV-1 may contribute to the production of both Aβ and hyperphosphorylated tau.
In a human neuronal brain organoid, a 3D model of brain structure, HSV-1-infected neurons caused surrounding neurons to produce Aβ. This finding indicates that HSV-1 indirectly influences Aβ production.
The team used metagenomic sequencing targeted for non-human genetic material and detected HSV-1 DNA in all postmortem human brain samples (n = 3, 3 no AD and advanced hippocampi with AD). They identified the expression of at least 15 HSV-1 proteins in AD brain samples, with ICP27 expression significantly increasing as the disease progressed. We found that ICP27 colocalized significantly with p-tau and that tau phosphorylation reduced ICP27 expression. Its inhibition or deletion renders the virus incapable of replication, underscoring its essential role in the HSV-1 life cycle, which is conserved across all human herpes viruses.
The study found microglial expression of ICP27 and p-tau. Additionally, ICP27 may be exposed to microglia, which promote inflammation and respond to HSV-1 via cGAS-STING by engulfing ICP27-laden neurons or by direct effect. These findings suggest a potential anti-herpetic role for the interaction between ICP27 and p-tau in microglia. We recently found that microglial p-tau (P301S mutation) activates cGAS and STING and elicits antiviral interferons. Furthermore, secreted tau can activate the polyglutamine binding protein 1 (PQBP1) and activate the cGAS-STING.
The next step was to study miniature models of human brains in a Petri dish, which suggested that HSV-1 infection could modulate the brain’s tau protein to either increase or decrease its function, both of which appeared to protect human neurons against death after they become infected.
Reference: Hyde VR, Zhou C, Fernandez JR, Bar DZ, D’Aiuto L, Shemesh OA. Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease. Cell Rep. 2025. doi:10.1016/j.celrep.2024.115109
