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

Author:

Wahl Devin12ORCID,Smith Meghan E.12,McEntee Cali M.12,Cavalier Alyssa N.12,Osburn Shelby C.12,Burke Samuel D.12,Grant Randy A.12,Nerguizian David3,Lark Daniel S.1,Link Christopher D.4,LaRocca Thomas J.12ORCID

Affiliation:

1. Department of Health and Exercise Science Colorado State University Fort Collins Colorado USA

2. Center for Healthy Aging Colorado State University Fort Collins Colorado USA

3. Department of Biochemistry and Molecular Genetics University of Colorado School of Medicine Aurora Colorado USA

4. Department of Integrative Physiology University of Colorado Boulder Boulder Colorado USA

Abstract

AbstractAging 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.

Funder

National Institute on Aging

Publisher

Wiley

Subject

Cell Biology,Aging

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