Alzheimer’s disease (AD) has traditionally been diagnosed based on the presence of β-amyloid plaques and hyperphosphorylated tau (p-tau) in the brain. Recent research suggests that infections, particularly herpes simplex virus 1 (HSV-1), may play a role in AD development. A new study led by Or Shemesh, PhD, assistant professor of ophthalmology at the University of Pittsburg, investigated how HSV-1 contributes to AD pathology, using advanced techniques like metagenomics, mass spectrometry, and western blotting to identify HSV-1-associated proteins in human brain tissue.
The study found a strong link between ICP27, a protein produced by HSV-1, and the severity of Alzheimer's disease. Notably, ICP27 colocalized with p-tau but not with Aβ, indicating a unique relationship between HSV-1 infection and tau pathology. The research team also observed that when human brain organoids were infected with HSV-1, tau phosphorylation increased. An intriguing finding was that p-tau reduced ICP27 expression, significantly decreasing neuronal death from 64% to just 7%. This suggests that tau phosphorylation might act as a protective response against viral infection, particularly in the context of AD.
Further investigation into the cGAS-STING-TBK1 immune pathway revealed that NF-κB and IRF-3 colocalized with ICP27 and p-tau in Alzheimer's brains. Experimental activation of the STING pathway enhanced tau phosphorylation, while inhibiting TBK1 prevented it. These findings point to tau phosphorylation, driven by the cGAS-STING pathway, as a possible immune response mechanism in AD, with HSV-1 infection potentially contributing to neurodegeneration.
Understanding the Mechanisms
β-amyloid plaques are clumps of protein that build up between brain cells in Alzheimer's disease disrupting communication between cells and cause brain damage.
P-tau is important for brain cell function, but when it happens too much (hyperphosphorylation), it causes tau to form harmful tangles. These tangles damage brain cells and are a key feature of AD. The researchers are studying how infections, like the HSV-1, might cause these tau problems.
ICP27 is a key protein produced by the HSV-1. It helps the virus replicate, avoid immune detection, and interact with the host cell in ways that may be linked to diseases like Alzheimer's disease, where it may affect tau protein.
cGAS-STING-TBK1 pathway is an immune response system that detects viral DNA and activates a series of reactions to protect the body. It's important in both fighting infections and, as recent research suggests, in neurodegenerative diseases like Alzheimer’s
NF-κB is mainly involved in inflammation and immune responses.
IRF-3 is involved in triggering antiviral defenses and inflammation
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's 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's disease,” he said. “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.”
The study also uncovered new insights into tau phosphorylation’s role as an innate immune response. Shemesh explained, “Tau protein might act as a double-edged sword in Alzheimer's 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's progression.” This dual nature of tau phosphorylation—as both protective and potentially toxic—has important implications for Alzheimer's 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 noted. “This shifts the focus of Alzheimer's 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's 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's, we need longitudinal studies to establish causal links between viral exposure and disease progression,” he said. “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's pathology, but before we can reach definitive conclusions, we need to conduct these studies.”
The work of Shemesh and his team contributes to a growing body of evidence suggesting that viral infections, particularly HSV-1, could play a role in Alzheimer’s progression. Their findings highlight the intricate connections between viral activity, tau phosphorylation, and the cGAS-STING-TBK1 immune response. As Shemesh concluded, by targeting specific molecular pathways and modulating the immune response, researchers could slow Alzheimer's progression and possibly even alter its course. While much more work is needed to validate these results, these studies open the door for new therapeutic approaches, including antiviral strategies that could one day target HSV-1 in the treatment of Alzheimer’s disease.
Reference
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
