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"Despite decades of study, neuroscientists aren’t sure exactly why some people develop the clumps of β-amyloid and tangles of phosphorylated tau proteins that are the hallmarks of Alzheimer’s disease. Now, a study adds to the support for a controversial hypothesis that viruses, especially those that cause herpes, may exacerbate or even trigger the neurodegenerative disease. ...
To further investigate this idea, researchers looked for HSV-1 proteins in postmortem brain samples from people with and without Alzheimer’s disease. They found bits of the virus in the same places as phosphorylated tau, suggesting an association. When they introduced the virus into cultured mini-brains grown from stem cells (known as organoids), levels of tau increased—and this rise helped suppress the infection. ..."
To further investigate this idea, researchers looked for HSV-1 proteins in postmortem brain samples from people with and without Alzheimer’s disease. They found bits of the virus in the same places as phosphorylated tau, suggesting an association. When they introduced the virus into cultured mini-brains grown from stem cells (known as organoids), levels of tau increased—and this rise helped suppress the infection. ..."
From the highlights and abstract:
"Highlights
• 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
Summary
Alzheimer’s disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (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, nuclear factor (NF)-κB 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."
Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease (open access)
Graphical abstract:
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