Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection
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Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.
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In this framework, neuroinflammatory AD symptoms are the result of Aβ oligomerization that encases pathogens following infection, sequestering them away from an opportunity to infect brain tissue.
“In this framework, neuroinflammatory AD symptoms are the result of Aβ oligomerization that encases pathogens following infection, sequestering them away from an opportunity to infect brain tissue [105,106].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [105]
Aβ is an antimicrobial peptide that protects the body from fungal and bacterial infections; oAβ binds to herpesvirus surface glycoprotein and protects 5×FAD mice from HSV-1 by accelerating Aβ deposition.
“Of note, recent studies showed that Aβ is an antimicrobial peptide that protects the body from fungal and bacterial infections. oAβ binds to herpesvirus surface glycoprotein and protects 5 × FAD mice from HSV-1 by accelerating Aβ deposition [536].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [536]
AD is associated with viral infection.
“Interestingly, several recent studies suggest that AD is associated with viral infection (47, 48).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [47]
Parenchymal Aβ in 5xFAD mice decreases mortality after direct intracerebral HSV inoculation.
“Similarly, presence of parenchymal Aβ in 5xFAD mice results in decreased mortality following direct intracerebral HSV inoculation.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Eimer et al., 2018
Brain areas with HSV-1 infection show increased Aβ deposition.
“Areas of brain parenchyma containing deposits of HSV-1 infection also demonstrated increased Aβ deposition (Eimer et al., 2018).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Eimer et al., 2018
The implication of herpesviridae in late-onset Alzheimer's disease is probably due to increased amyloid-β amyloidosis.
“probably due to the increased amyloid-β amyloidosis [37].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [37]
Aβ peptides interact with and entrap various bacterial strains and viruses, such as HSV1 and HSV6, and block their entry into host cells to replicate.
“Aβ peptides are able to interact and entrap various bacterial strains and viruses, such as HSV1 and HSV6, block their entry into the host cells to replicate.402–404”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [403]
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Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
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Amyloid-β: A double agent in Alzheimer's disease?
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Viral pathogens increase risk of neurodegenerative disease
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Pathogenesis, Animal Models, and Drug Discovery of Alzheimer’s Disease
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- Authors
- Eimer, W. A., Vijaya Kumar, D. K., Navalpur Shanmugam, N. K., Rodriguez, A. S., Mitchell, T., Washicosky, K. J., György, B., Breakefield, X. O., Tanzi, R. E., & Moir, R. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Tanzi, Rudolph E.
- Moir, Robert D.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 99
- Issue
- 1
- Pages
- 56-63.e3
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6075814
- OpenAlex
- W2805303487
- Cited by
- 674
- References
- 60
- Citations by year
- 2026: 59 · 2025: 84 · 2024: 66 · 2023: 66 · 2022: 95 · 2021: 108 · 2020: 96 · 2019: 77 · 2018: 23
- FWCI
- 52.11
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-12-19)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cure Alzheimer's Fund
- Good Ventures
- NIH (5R01AI081990-02)
- Helmsley Charitable Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- Alzheimer's disease, amyloid-beta, herpesvirus, herpes simplex virus type 1, human herpesvirus 6, amyloid-beta oligomers, innate immunity, neurotropic viruses, 5xFAD mice
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Brain, Cells, Cultured, Disease Models, Animal, Herpesviridae, Humans, Mice, Transgenic, Neurons, Herpesvirus 6, Human, Amyloid beta-Peptides, Neurofibrillary Tangles, Herpesvirus 1, Human, Encephalitis, Viral, Roseolovirus Infections, Encephalitis, Herpes Simplex, Mice, Plaque, Amyloid
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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