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Cited by 36Alzheimer's disease research and treatmentsRedox biology and oxidative stressNeurological Disease Mechanisms and Treatments

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

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Protto, Virginia, Tramutola, Antonella, Fabiani, Marco, Marcocci, Maria Elena, Napoletani, Giorgia, Iavarone, Federica, Vincenzoni, Federica, Castagnola, Massimo +4 more·2020·Microorganisms
DOI 10.3390/microorganisms8070972PMC PMC7409037
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Abstract

Compelling evidence supports the role of oxidative stress in Alzheimer’s disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Herein, we analyzed, through biochemical and redox proteomic approaches, the mouse model of recurrent HSV-1 infection we previously set up, to investigate whether multiple virus reactivations induced oxidative stress in the mouse brain and affected protein function and related intracellular pathways. Following multiple HSV-1 reactivations, we found in mouse brains increased levels of oxidative stress hallmarks, including 4-hydroxynonenal (HNE), and 13 HNE-modified proteins whose levels were found significantly altered in the cortex of HSV-1-infected mice compared to controls. We focused on two proteins previously linked to AD pathogenesis, i.e., glucose-regulated protein 78 (GRP78) and collapsin response-mediated protein 2 (CRMP2), which are involved in the unfolded protein response (UPR) and in microtubule stabilization, respectively. We found that recurrent HSV-1 infection disables GRP78 function and activates the UPR, whereas it prevents CRMP2 function in mouse brains. Overall, these data suggest that repeated HSV-1 reactivation into the brain may contribute to neurodegeneration also through oxidative damage.

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  • HSV-1 has been detected in postmortem Alzheimer's disease brains, where it colocalizes with amyloid plaques; experimental models demonstrate that HSV-1 infection induces amyloid and tau pathology, and repeated viral reactivations accelerate cognitive deficits.

    “HSV-1 has been detected in postmortem AD brains, where it colocalizes with amyloid plaques. Experimental models demonstrate that HSV-1 infection induces amyloid and tau pathology, while repeated viral reactivations accelerate cognitive deficits [167].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [167]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Herpesvirus infections are associated with higher dementia incidence, whereas long-term use of antiherpetic medications such as acyclovir significantly reduces Alzheimer's disease risk.

    “Epidemiological studies provide further support, whereby herpesvirus infections are associated with higher dementia incidence, whereas long-term use of antiherpetic medications such as acyclovir significantly reduces AD risk [167].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [167]

    The Introduction reports population-based clinical evidence supporting HSV-1 reactivation as a potential risk factor for Alzheimer’s disease. It does not establish higher dementia incidence for herpesviruses generally, and the searched passages do not report that long-term antiherpetic treatment, including acyclovir, reduces Alzheimer’s risk. No page numbers were available in our copy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Protto, V., Tramutola, A., Fabiani, M., Marcocci, M. E., Napoletani, G., Iavarone, F., Vincenzoni, F., Castagnola, M., Perluigi, M., Di Domenico, F., De Chiara, G., & Palamara, A. T.
Affiliations
  • Istituto Pasteur (IT)
  • Sapienza University of Rome (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • Institute of Chemistry of Molecular Recognition (IT)
  • Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy
  • Institute of Translational Pharmacology, National Research Council (CNR), 00133 Rome, Italy
ORCID
Venue
Microorganisms
Publisher
MDPI AG
Published
2020-06-29
Volume
8
Issue
7
Pages
972
ISSN
2076-2607 (ISSN-L)
DOI
10.3390/microorganisms8070972
PMC
PMC7409037
OpenAlex
W3039537783
Cited by
36
References
8
Citations by year
2026: 4 · 2025: 9 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 2
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Microorganisms (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Italian Ministry of Instruction, University and Research (PRIN20179JHMZ_006)
  • Ateneo2019 (RP11916B8696E5EC)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
herpes simplex virus type 1, viral reactivation, Alzheimer's disease, oxidative stress, protein oxidation, 4-hydroxynonenal, redox proteomics, GRP78, unfolded protein response, CRMP2, microtubule stabilization, neurodegeneration, recurrent viral infections, mouse brain

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