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Cited by 40Alzheimer's disease research and treatmentsGenetics, Aging, and Longevity in Model OrganismsNeuroinflammation and Neurodegeneration Mechanisms

The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction

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Wahl, Devin, Smith, Meghan E., McEntee, Cali M., Cavalier, Alyssa N., Osburn, Shelby C., Burke, Samuel D., Grant, Randy A., Nerguizian, David +3 more·2023·Aging Cell
DOI 10.1111/acel.13798PMC PMC10186603
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Abstract

Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age‐related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild‐type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans ; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age‐related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

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Cited by

Sorted by citations

Authors
Wahl, D., Smith, M. E., McEntee, C. M., Cavalier, A. N., Osburn, S. C., Burke, S. D., Grant, R. A., Nerguizian, D., Lark, D. S., Link, C. D., & LaRocca, T. J.
Affiliations
  • Colorado State University (US)
  • University of Colorado Anschutz (US)
  • University of Colorado Boulder (US)
Corresponding author
LaRocca, Thomas J.
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2023-03-22
Volume
22
Issue
5
Pages
e13798-e13798
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13798
PMC
PMC10186603
OpenAlex
W4360599647
Cited by
40
References
14
Citations by year
2026: 13 · 2025: 17 · 2024: 7 · 2023: 3
FWCI
7.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CU Scholar (University of Colorado Boulder) (submittedVersion, cc-by)
Funders
National Institute on Aging (AG060302, AG070562, AG078859, F32AG069361)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
lamivudine, reverse transcriptase inhibitors, brain aging, age-related cognitive decline, neuroinflammation, Alzheimer's disease, tauopathy, neuronal health, neurodegeneration, Caenorhabditis elegans
MeSH terms
Neuroinflammatory Diseases, Aging, Alzheimer Disease, Animals, Brain, Humans, Reverse Transcriptase Inhibitors, Mice, Cognitive Dysfunction

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