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Cited by 79Alzheimer's disease research and treatmentsChromosomal and Genetic VariationsGenetics, Aging, and Longevity in Model Organisms

Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system

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Ramirez, Paulino, Zuniga, Gabrielle, Sun, Wenyan, Beckmann, Adrian, Ochoa, Elizabeth, DeVos, Sarah L., Hyman, Bradley, Chiu, Gabriel +6 more·2022·Progress in Neurobiology
DOI 10.1016/j.pneurobio.2021.102181PMC PMC8712387

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Abstract

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. Using two complementary approaches, we find that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy and provides support for ongoing therapeutic efforts targeting transposable element activation in patients with Alzheimer's disease.

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  • Three different mouse models of tauopathy feature disease stage-dependent robust elevation of retrotransposon transcripts, while retrotransposons lack differential expression in a mouse model of Aβ pathology.

    “Similarly, three different mouse models of tauopathy feature disease stage–dependent robust elevation of retrotransposon transcripts, while retrotransposons lack differential expression in a mouse model of Aβ pathology (Ramirez et al. 2022).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ramirez et al. 2022

    The Results section reports age-dependent elevation of retrotransposon transcripts across three mouse models of tauopathy. But it does not report a complete absence of differential expression in the APP/PS1 amyloid model: it detects three differentially expressed retrotransposons, two of them decreased. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • Subsequent studies in brains of tau transgenic mice indicate that a tau-induced increase in LINE-1 and ERV1/ERVK DNA copy number is conserved in mammalian systems and is dependent upon disease stage.

    “Subsequent studies in brains of tau transgenic mice indicate that a tau-induced increase in LINE-1 and ERV1/ERVK DNA copy number is conserved in mammalian systems and is dependent upon disease stage (Ramirez et al. 2022).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ramirez et al. 2022

    The Results section ('Transposable element DNA copy number is elevated in tau transgenic mice'; page unavailable) reports increased L1, ERVK and ERV1 DNA copy number in tau transgenic mouse brains, particularly at 12 months. It concludes that the increase is age-dependent, but does not establish that DNA copy number depends on disease stage independently of age. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Similarly, tau transgenic mice were found to have an increased DNA copy number of some retrotransposons that are thought to be transpositionally incompetent.

    “Similarly, tau transgenic mice were found to have an increased DNA copy number of some retrotransposons that are thought to be transpositionally incompetent (Ramirez et al. 2022).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ramirez et al. 2022

    The Results section reports increased retrotransposon DNA copy number in brains of tau transgenic mice. It also says some NanoString probes detect both active and inactive members, but does not establish that the increased copies specifically belong to transpositionally incompetent retrotransposons; the Discussion notes that the assays cannot distinguish genomic from episomal DNA. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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 Ramirez et al. 2022

  • Cells exhibiting Gag elevation in brains of tau transgenic mice are not the cells that also harbor disease-associated phospho-tau, suggesting that Gag elevation is non-cell autonomous.

    “Cells exhibiting Gag elevation in brains of tau transgenic mice are not the cells that also harbor disease-associated phospho-tau, suggesting that Gag elevation is non–cell autonomous (Ramirez et al. 2022).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ramirez et al. 2022

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Authors
Ramirez, P., Zuniga, G., Sun, W., Beckmann, A., Ochoa, E., DeVos, S. L., Hyman, B., Chiu, G., Roy, E. R., Cao, W., Orr, M., Buggia-Prevot, V., Ray, W. J., & Frost, B.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • Harvard University (US)
  • Baylor College of Medicine (US)
  • W. G. (Bill) Hefner VA Medical Center (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Frost, Bess
ORCID
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2022-01
Volume
208
Pages
102181
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/j.pneurobio.2021.102181
PMC
PMC8712387
OpenAlex
W3206327767
Cited by
79
References
12
Citations by year
2026: 7 · 2025: 24 · 2024: 22 · 2023: 17 · 2022: 8 · 2021: 1
FWCI
7.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Neurobiology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (BF, RF1 NS112391)
  • NIA (T32 AG00022, RF1 AG057587, T32 AG021890)
  • NIGMS (R25 GM095480, T32 GM113896)
  • BrightFocus Foundation
  • Boler Family Foundation
  • Rainwater Charitable Foundation
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
transposable elements, brain aging, tauopathy, Alzheimer's disease, endogenous retroviruses, retrotransposons, intracisternal A-particle, retrotransposition, neurotoxicity, transposable element copy number, tau transgenic mice, central nervous system
MeSH terms
Aging, Animals, Brain, Disease Models, Animal, DNA Transposable Elements, Humans, Mammals, Mice, Transgenic, tau Proteins, Mice

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