Herpes Viruses May Fuel the Development of Alzheimer Disease

Or Shemesh, PhD

(Credit: LinkedIn)

This story was originally published by our sister publication, ContagionLive.

Alzheimer disease (AD) has traditionally been identified by the presence of β-amyloid plaques and hyperphosphorylated tau (p-tau) in the brain. However, recent studies suggest that infections, particularly herpes simplex virus 1 (HSV-1), may influence AD development. A new investigation led by Or Shemesh, PhD, assistant professor of ophthalmology at the University of Pittsburgh, examined the role of HSV-1 in AD pathology using advanced techniques such as metagenomics, mass spectrometry, and western blotting to detect HSV-1-associated proteins in human brain tissue.¹

The study revealed a significant association between ICP27, a protein produced by HSV-1, and the severity of AD. Interestingly, ICP27 was found to colocalize with p-tau but not with Aβ, highlighting a specific link between HSV-1 infection and tau pathology. In experiments using human brain organoids infected with HSV-1, researchers observed increased tau phosphorylation. Remarkably, p-tau was shown to suppress ICP27 expression, reducing neuronal death from 64% to just 7%. This suggests that tau phosphorylation might serve as a protective response to viral infection in AD.

In a recent email interview with Shemesh, he elaborated on the significance of these findings, explaining how his team's research could alter the way we approach Alzheimer treatment. “Our study highlights that the cGAS-STING-TBK1 pathway, known for its role in innate immune responses, is implicated in tau phosphorylation during HSV-1 infection in Alzheimer disease,” he told to ContagionLive^®. “This pathway's involvement suggests that it could be a novel therapeutic target in neurodegeneration. Modulating this pathway might help in controlling the hyperphosphorylation of tau, potentially slowing or altering disease progression. That said, only after these studies are conducted will we be able to predict the therapeutic efficacy of such strategies.”

Further analysis of the cGAS-STING-TBK1 immune pathway showed that NF-κB and IRF-3 colocalized with ICP27 and p-tau in AD brains. Activating the STING pathway enhanced tau phosphorylation, while inhibiting TBK1 prevented it. These findings propose that tau phosphorylation, driven by the cGAS-STING pathway, may function as an immune defense mechanism in AD, with HSV-1 potentially contributing to neurodegeneration.

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The study also uncovered new insights into tau phosphorylation’s role as an innate immune response. Shemesh explained in the interview, “Tau protein might act as a double-edged sword in Alzheimer disease, particularly in its response to HSV-1 infection. On one hand, tau phosphorylation appears to block the spread of herpesvirus, providing a protective effect against the virus. On the other hand, this same process leads to the formation of toxic tau tangles, which are harmful to neurons and contribute to Alzheimer progression.” This dual nature of tau phosphorylation—as both protective and potentially toxic—has important implications for Alzheimer treatment strategies.

Shemesh emphasized that the innate immune response triggered by tau phosphorylation may be beneficial early on but could become toxic if it persists. “Our findings suggest that this innate immune response, while initially beneficial, might become toxic over time,” he said. “This shifts the focus of Alzheimer treatments toward a more nuanced approach—one that seeks to preserve tau's antiviral functions while preventing or mitigating its neurotoxic effects. Future therapies could aim to fine-tune this balance, potentially leading to more effective treatments for Alzheimer disease.”

Despite these promising findings, Shemesh stressed the importance of longitudinal studies to establish causal links between viral exposure and AD progression. “To fully understand the relationship between viral infections and Alzheimer, we need longitudinal studies to establish causal links between viral exposure and disease progression,” he told to ContagionLive. “Further research should focus on elucidating the molecular mechanisms, particularly how viral infections activate immune pathways like cGAS-STING to drive tau phosphorylation. Additionally, exploring therapeutic interventions, including antiviral drugs and immune modulators, could pave the way for effective treatments targeting viral contributions to Alzheimer pathology, but before we can reach definitive conclusions, we need to conduct these studies.”

Shemesh and his team’s research adds to the growing evidence that viral infections, particularly HSV-1, may influence the progression of AD. The findings emphasized the complex interplay between viral activity, tau phosphorylation, and the cGAS-STING-TBK1 immune pathway. According to Shemesh, targeting specific molecular pathways and modulating the immune response could help slow AD progression and potentially change its trajectory. Although further studies are required to confirm these results, this research paves the way for novel therapeutic strategies, including antiviral treatments that may one day address HSV-1 in AD management.

REFERENCES
1. Hyde VR, Zhou C, Fernandez JR, et al. Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease. Cell Rep. January 2, 2025;10.1016/j.celrep.2024.115109. doi:10.1016/j.celrep.2024.115109