Hyde VR, Zhou C, Fernandez JR, Chatterjee K, Ramakrishna P, Lin A, Fisher GW, Çeliker OT, Caldwell J, Bender O, Sauer PJ, Lugo-Martinez J, Bar DZ, D'Aiuto L, Shemesh OA. Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease. Cell Rep. 2024 Dec 26;:115109. Epub 2024 Dec 26 PubMed.
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Neural Stem Cell Institute
This study reinforces the concept that infections, including herpesviruses, can act as a trigger or accelerator for AD pathology, potentially through mechanisms involving neuroinflammation, tauopathy, and Aβ deposition. The authors demonstrate that herpesvirus infection exacerbates tau hyperphosphorylation and aggregation, which are hallmark features of AD pathology.
We have observed similar results in two-dimensional and three-dimensional cultures, with HSV-1 infection promoting tau phosphorylation and oligomerization, further supporting the link between viral infection and tau pathology. The findings that phosphorylated tau (p-tau) was protective in lowering viral protein levels and preserving neurons raise intriguing questions about the dual nature of tau in the context of infections. This aligns with the hypothesis that tau, like Aβ, may initially serve a protective function, but that prolonged or dysregulated responses could transition to pathology.
The current study attributes antiviral effects to p-tau. Unfortunately, a tau knockout control was unavailable, so it remains to be seen if a compensatory or redundant mechanism may also contribute to the observed effects.
This is an important study that advances our understanding of the interplay between infections and tau pathology in AD, and further underscores that continued research is needed to elucidate the underlying mechanisms and therapeutic implications.
View all comments by David ButlerASU-Banner, Neurodegenerative Disease Research Center
This exciting and provocative new study by Hyde et al. substantially extends our understanding of the interactions between HSV-1 and the neuropathological underpinnings of Alzheimer's disease. The study leverages the de-crowding expansion pathology approach to examine postmortem human brain tissue to examine the spatial distribution of HSV-1 proteins, which appears to reduce false-positive fluorescent signals and, notably, identifies viral proteins in each of the six samples studied. From here, the authors report the co-localization of immediate early protein ICP27 with hyperphosphorylated tau (p-tau). Through a series of brain organoid, neuronal culture, and kinase modulation studies, the authors demonstrate that HSV-1 infection significantly upregulates p-tau, mediated by cGAS-STING activation, and that this upregulation appears to protect against neuronal death in the presence of HSV-1, perhaps by inhibiting ICP27 expression.
This expanded picture of a role for p-tau as an innate immune effector molecule with potent activity against HSV-1 is consistent with the antimicrobial protection hypothesis (Moir et al., 2018), which proposed Aβ deposition as an innate immune response to invading pathogens. The results of this current work extend this idea to more concretely incorporate p-tau within this same paradigm. It is intriguing that the authors observed that HSV-1 associated with p-tau, though not with extracellular Aβ-amyloid or Aβ oligomers. As the authors note in the discussion, this may simply reflect an immune specialization directed against predominantly intracellular (i.e. viral) pathogens.
Since extracellular Aβ plaques may be seeded intracellularly in some cases, it may be informative to exclude a co-localization of ICP27 with intracellular Aβ (Hu et al., 2009; Friedrich et al., 2010). Alternatively, it may be that the mode of HSV-1 infection in the postmortem samples studied was indeed an abortive infection, such that other viral proteins more likely to trigger Aβ fibrilization, such as HSV-1 glycoprotein gB (Eimer et al., 2018), may not have been abundantly present. In our own study of (active, lytic) HSV-1 infections of brain organoids, we observed an acceleration of both intracellular Aβ42 and p-tau following infection (Olson et al., 2024). Determining whether different HSV-1 proteins can trigger varying combinations of Aβ and p-tau responses may warrant future investigation.
In addition to offering new insights into HSV-1, the study lays out constructive approaches to studying other pathogens that may be relevant to neurodegeneration. We recently reported a multi-tissue association between human Cytomegalovirus (HCMV), Immunoglobulin G4, and CD83(+) microglia in a subset of patients with Alzheimer's disease (Readhead et al., 2024; Jan 2025 news). We noted that HCMV infection of brain organoids increased accumulation of intracellular Aβ and p-tau. Further study of co-localization between additional viruses and p-tau, activation of cGAS-STING, and examining any antiviral effects of p-tau against other viruses, including HCMV, may be fruitful.
References:
Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 2018 Dec;14(12):1602-1614. Epub 2018 Oct 9 PubMed.
Hu X, Crick SL, Bu G, Frieden C, Pappu RV, Lee JM. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9. PubMed.
Friedrich RP, Tepper K, Rönicke R, Soom M, Westermann M, Reymann K, Kaether C, Fändrich M. Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1942-7. PubMed.
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, György B, Breakefield XO, Tanzi RE, Moir RD. Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron. 2018 Jul 11;99(1):56-63.e3. PubMed.
Olson MN, Dawes P, Murray LF, Barton NJ, Sundstrom J, Orszulak AR, Chigas SM, Tran K, Aylward AJ, Caliandro MF, Riechers S-P, Afshari K, Wang Q, Garber M, Humphries F, Orzalli MH, Golenbock DT, Heneka MT, Oh HS, Church GM, Young-Pearse TL, Knipe DM, Readhead B, Chan Y, Lim ET. Development of a high-throughput, quantitative platform using human cerebral organoids to study virus-induced neuroinflammation in Alzheimer's disease. 2024 Mar 23 10.1101/2024.03.21.585957 (version 1) bioRxiv.
Readhead BP, Mastroeni DF, Wang Q, Sierra MA, de Ávila C, Jimoh TO, Haure-Mirande JV, Atanasoff KE, Nolz J, Suazo C, Barton NJ, Orszulak AR, Chigas SM, Tran K, Mirza A, Ryon K, Proszynski J, Najjar D, Dudley JT, Liu ST, Gandy S, Ehrlich ME, Alsop E, Antone J, Reiman R, Funk C, Best RL, Jhatro M, Kamath K, Shon J, Kowalik TF, Bennett DA, Liang WS, Serrano GE, Beach TG, Van Keuren-Jensen K, Mason CE, Chan Y, Lim ET, Tortorella D, Reiman EM. Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain. Alzheimers Dement. 2024 Dec 19; Epub 2024 Dec 19 PubMed.
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