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Cited by 73Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAmyotrophic Lateral Sclerosis Research

Pathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation

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Ochoa, Elizabeth, Ramirez, Paulino, Gonzalez, Elias, De Mange, Jasmine, Ray, William J., Bieniek, Kevin F., Frost, Bess·2023·Science Advances
DOI 10.1126/sciadv.abq5423PMC PMC9821943
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Abstract

Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau–induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau–induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element–derived dsRNA in the adult brain.

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  • Transposable elements may also drive neuroinflammation by forming double-stranded RNA in astrocytes.

    “Transposable elements may also drive neuroinflammation by forming double-stranded RNA in astrocytes [130].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [130]

    The Results report retrotransposon-derived dsRNA in tau-transgenic fly brains, and the Discussion reports dsRNA accumulation in astrocytes. But the Discussion says astrocytes might produce, sequester, or fail to degrade that dsRNA; its proposed model instead has the dsRNA forming in neurons and then being taken up by astrocytes. Formation specifically in astrocytes is therefore not established. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Pan-neuronal expression of human tau causes dsRNA accumulation in astrocyte-like cells of the Drosophila brain.

    “Pan-neuronal expression of human tau causes dsRNA accumulation in astrocyte-like cells of the Drosophila brain.”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ochoa et al. 2023

  • In recent years, studies in Drosophila, mice, and humans have suggested that pathogenic forms of tau drive neurodegeneration by activating retrotransposons.

    “In recent years, studies in Drosophila, mice, and humans have suggested that pathogenic forms of tau drive neurodegeneration by activating retrotransposons (Guo et al. 2018, Ochoa et al. 2023, Ramirez et al. 2022, Sun et al. 2018, Wahl et al. 2023).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ochoa et al. 2023

  • Astrocytic dsRNA deposition is conserved in brains of tau transgenic mice and in patients with AD or PSP and occurs alongside elevation of the RIG-I-like dsRNA sensor MDA5.

    “Astrocytic dsRNA deposition is conserved in brains of tau transgenic mice and in patients with AD or PSP and occurs alongside elevation of the RIG-I-like dsRNA sensor MDA5 (Ochoa et al. 2023), consistent with previous reports of elevated RIG-I in the brains of patients with mild cognitive impairment (de Rivero Vaccari et al. 2014).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ochoa et al. 2023

  • Studies in Drosophila indicate that the negative effects of tau on the lamin nucleoskeleton result in the decondensation of heterochromatin and a toxic, neuroinflammatory activation of retrotransposons.

    “Studies in Drosophila indicate that the negative effects of tau on the lamin nucleoskeleton result in the decondensation of heterochromatin (Frost et al. 2014) and a toxic, neuroinflammatory activation of retrotransposons (Ochoa et al. 2023, Sun et al. 2018).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ochoa et al. 2023

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Cited by

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Authors
Ochoa, E., Ramirez, P., Gonzalez, E., De Mange, J., Ray, W. J., Bieniek, K. F., & Frost, B.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, TX, USA.
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Frost, Bess
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2023-01-06
Volume
9
Issue
1
Pages
eabq5423-eabq5423
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abq5423
PMC
PMC9821943
OpenAlex
W4313625436
Cited by
73
References
15
Citations by year
2026: 18 · 2025: 29 · 2024: 18 · 2023: 8
FWCI
12.96
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NIH P40OD018537, P40OD018537)
  • National Institute on Aging (P30AG066546)
  • National Cancer Institute
  • National Institute of General Medical Sciences (GM095480, R25GM095480)
  • National Institute of Neurological Disorders and Stroke (RF1NS112391)
  • National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
tauopathy, Alzheimer's disease, progressive supranuclear palsy, retrotransposons, double-stranded RNA, neuroinflammation, astrocytes, neurodegeneration, Drosophila model, tau transgenic mice, postmortem brain, dsRNA sensing
MeSH terms
Neuroinflammatory Diseases, Adult, Alzheimer Disease, Animals, Brain, DNA Transposable Elements, Drosophila, Heterochromatin, Humans, Mice, Transgenic, RNA, Double-Stranded, tau Proteins, Retroelements, Tauopathies, Mice

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