09 Jan 2025

Some researchers believe the brain makes Aβ to help fight bacterial and fungal invaders. Now comes evidence that p-tau may take on a similar role against viruses. In the January 2 Cell Reports, scientists led by Or Shemesh at Hebrew University of Jerusalem reported finding high expression in Alzheimer’s disease brain of a herpes simplex I protein. Called ICP27, its abundance rose with disease severity, and it co-localized with p-tau. In neuronal cultures, HSV-1 infection promoted p-tau formation via the antiviral cGAS-STING pathway. The twist? This p-tau then suppressed ICP27, hinting that neurons may initially ramp up p-tau production to combat viral infection.

What if p-tau stays up long-term? David Butler at the Neural Stem Cell Institute in Rensselaer, New York, thinks that spells danger. “This study reinforces the concept that infections, including herpes viruses, can act as a trigger or accelerator for AD pathology, potentially through mechanisms involving neuroinflammation, tauopathy, and Aβ deposition,” he wrote to Alzforum. Butler was not involved in the work, but he and colleague Eain Murphy at SUNY Upstate Medical University in Syracuse, New York, have likewise found that HSV-1 triggers tau phosphorylation. Their data were uploaded to bioRxiv on October 16 (Ijezie et al., 2024). 

“We believe the brain virome has a role in the etiology of AD,” Shemesh told Alzforum.

Viral Stopper? Viral infections trigger the antiviral cGAS-STING pathway. This activates TANK-binding kinase 1, which phosphorylates p-tau. The p-tau then suppresses viral proteins and protects neurons. [Courtesy of Hyde et al., Cell Reports.]

Previous studies have reported that infection by HSV-1, bacteria, or fungi triggered amyloidosis in the brain (Apr 2009 conference news; May 2016 news; Jun 2018 news). Fewer studies have examined tau changes in this context, though Andrea Bertke and colleagues at the Virginia-Maryland College of Veterinary Medicine reported that HSV-1 infection of cultured mouse neurons boosted p-tau levels (Powell-Doherty et al., 2020). 

HSV-1 is a common virus. During infection, its DNA incorporates into host chromosomes, where it lies dormant. An estimated two-thirds of adults worldwide carry these latent HSV-1 genes. Previous work found that an uptick in viral gene load correlated with AD, but whether these genes were translated into protein was unclear (Jun 2018 news).

Shemesh and colleagues wondered whether expression of viral proteins could contribute to AD. First author Vanesa Hyde, at the University of Pittsburgh School of Medicine, Pennsylvania, detected HSV-1 proteins in postmortem hippocampal samples from both AD and control brains. To quantify them and look for differences, she used de-crowding expansion pathology, a technique developed at MIT that spreads out proteins in tissues, thereby eliminating interfering fluorescence from aggregates of lipids and proteins and providing clearer signals (Valdes et al., 2024). This technique revealed that ICP27, but none of the other three viral proteins the authors examined, went up in AD. ICP27 acts as a master regulator for HSV-1, controlling viral protein expression, and is essential for viral replication (for review see Sandri-Goldin, 2011). 

ICP27 expression tracked with disease severity, with levels increasing from mild to advanced AD. In the entorhinal cortex, twice as many cells expressed ICP27 in advanced AD cases as in controls; in the hippocampus, three times as many. In control and mild AD brains, these cells were mostly neurons, but in advanced AD, microglia contained ICP27 as well. It was not clear if microglia expressed the protein, or merely ingested it by engulfing dying neurons.

ICP27 Begets p-Tau. In postmortem hippocampi from healthy controls (left), cells make little viral protein ICP27 (green) or p-tau (red). In hippocampi from mild AD brains (center), they make more of each, and these proteins occur together (arrows; overlay yellow). In advanced AD (right), ICP27 and p-tau are abundant and co-localized. [Courtesy of Hyde et al., Cell Reports.]

Intriguingly, ICP27 had no spatial relationship with amyloid plaques or Aβ oligomers. It did overlap with p-tau, however, with this co-localization increasing eightfold from control to advanced AD samples (image above).

To find out what ICP27 was doing, the authors used cultured cells. In human cerebral organoids, HSV-1 infection amped up tau expression and phosphorylation, particularly at serines 199 and 202. Pretreating with antiviral drugs prevented this.

How does HSV-1 do this? Viral infections are known to activate the cytosolic enzyme cGAS, a DNA sensor that is part of the innate immune system. In turn, cGAS activates a stimulator of interferon genes (STING), which switches on transcription factors and other downstream effectors, including TANK-binding kinase 1. The authors confirmed that this pathway was active in the same spots where ICP27 and p-tau were located in postmortem brain samples. In primary rodent neurons infected with HSV-1, when the authors artificially activated cGAS, p-tau abundance doubled, while adding a TBK1 inhibitor prevented any rise in p-tau. The cGAS-STING-TBK1 innate immune pathway controls production of p-tau after infection, the authors concluded.

What does this p-tau do? In rodent neurons, preventing p-tau formation via the TBK1 inhibitor doubled the amount of ICP27 in these cells. Conversely, transfecting these neurons with human tau bearing the phosphorylation-prone P301L mutation boosted p-tau and squelched ICP27 by 90 percent. In the latter case, the neuronal death rate plummeted from 83 to 7 percent, indicating that p-tau protects neurons from the negative effects of HSV-1, at least in the short term. Longer-term activation of cGAS-STING has been linked to neuronal damage and death (Apr 2023 conference news; Aug 2023 news).

"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),” Benjamin Readhead at Arizona State University, Tempe, wrote to Alzforum (comment below).

Murphy, at SUNY, was enthusiastic about this paper. He noted that it fills in mechanistic links between HSV-1 infection and AD. Murphy and Butler have produced similar data showing that ICP27 not only promotes p-tau, but also tau oligomers, a toxic form. “We’re in full agreement with what Or’s group has found,” Murphy told Alzforum.

Murphy believes that targeting ICP27, or developing a vaccine against HSV-1, might help prevent AD. Epidemiological studies have linked vaccination against several viruses, such as influenza, pneumonia, and herpes, to a lower incidence of the disease (Jul 2020 conference news; Feb 2021 news).

Knock the Organoid. A pneumatic cylinder (left) taps a three-dimensional neural tissue to simulate a blow to the head, while a piston jiggles a spring-loaded platform (right) to model repeated mild concussions. [Courtesy of Cairns et al., Science Signaling.]

If most adults carry HSV-1 DNA, why isn’t Alzheimer’s even more common? Shemesh speculated that environmental insults, such as new infections or head injuries, could reactivate HSV-1. A paper from David Kaplan at Tufts University in Medford, Massachusetts, and Ruth Itzhaki at the University of Oxford lends support to this version of the two-hit hypothesis of Alzheimer’s. In the January 7 Science Signaling, they reported that mechanical impacts can trigger expression of latent HSV-1 genes. They generated a three-dimensional, brain-like tissue in a culture dish using human induced neural stem cells, and infected it with HSV-1. Ten days later, they subjected this tissue to either a single direct impact, to mimic the cellular stress experienced during a blow to the head, or repetitive shaking, to model the effects of repeated mild concussions on brain tissue (image above). The repetitive injuries caused viral proteins to accumulate and led to inflammation, amyloidosis, and p-tau accumulation.

Davangere Devanand at Columbia University Irving Medical Center in New York noted that more research will be needed to fully establish a causal relationship between viral infections and amyloid and tau pathology. “If established, these findings may lead to therapeutic options to minimize the triggers for amyloid and tau formation, rather than the current strategy of directly reducing amyloid and tau burden itself,” he wrote to Alzforum.—Madolyn Bowman Rogers

Comments

1. • David Butler
     Neural Stem Cell Institute
   • Posted: 09 Jan 2025

   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 Butler
2. • Ben Readhead
     ASU-Banner, Neurodegenerative Disease Research Center
   • Posted: 09 Jan 2025

   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.

   View all comments by Ben Readhead

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References

News Citations

1. Prague: Aβ Rehabilitated as an Antimicrobial Protein? 1 Apr 2009
2. Like a Tiny Spider-Man, Aβ May Fight Infection by Cocooning Microbes 27 May 2016
3. Herpes Triggers Amyloid—Could This Virus Fuel Alzheimer’s? 29 Jun 2018
4. Aberrant Networks in Alzheimer’s Tied to Herpes Viruses 20 Jun 2018
5. By Unleashing Microglial cGAS, Tau STINGs Neurons 26 Apr 2023
6. With Age, Microglia Pump cGAS, Revving Harmful Inflammation 18 Aug 2023
7. Could Common Vaccines Protect Against Alzheimer’s Disease? 29 Jul 2020
8. Herpes Update—Virus Increases Dementia Risk in Sweden 28 Feb 2021

Paper Citations

1. Ijezie EC, Miller MJ, Hardy C, Jarvis AR, Czajka T, D'Brant L, Rugenstein N, Waickman A, Murphy E, Butler D. HSV-1 Infection Alters MAPT Splicing and Promotes Tau Pathology in Neural Models of Alzheimer's Disease. 2024 Oct 16 10.1101/2024.10.16.618683 (version 1) bioRxiv.
2. Powell-Doherty RD, Abbott AR, Nelson LA, Bertke AS. Amyloid-β and p-Tau Anti-Threat Response to Herpes Simplex Virus 1 Infection in Primary Adult Murine Hippocampal Neurons. J Virol. 2020 Apr 16;94(9) PubMed.
3. Valdes PA, Yu CJ, Aronson J, Ghosh D, Zhao Y, An B, Bernstock JD, Bhere D, Felicella MM, Viapiano MS, Shah K, Chiocca EA, Boyden ES. Improved immunostaining of nanostructures and cells in human brain specimens through expansion-mediated protein decrowding. Sci Transl Med. 2024 Jan 31;16(732):eabo0049. Epub 2024 Jan 31 PubMed.
4. Sandri-Goldin RM. The many roles of the highly interactive HSV protein ICP27, a key regulator of infection. Future Microbiol. 2011 Nov;6(11):1261-77. PubMed.
5. 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.

Further Reading

News

1. Dementia à la Mold? Fungi May Lurk in Alzheimer’s Brains 16 Oct 2015
2. An Antimicrobial Approach to Treating Alzheimer’s? 28 Jan 2019
3. When Host Proteins Coat Virus, Amyloid Fibrils Form 29 May 2019
4. New Data Questions Herpes-Alzheimer’s Connection 22 Jan 2021
5. More Data on Herpes and Alzheimer’s Disease 16 Apr 2021
6. Nothing to Sneeze At: Viruses Raise Risk of Neurodegenerative Disease 2 Feb 2023
7. Can Human Cytomegalovirus Infections Spark Alzheimer’s Pathology? 2 Jan 2025