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

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 Alzhei...

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Autores principales: Wahl, Devin, Smith, Meghan E., McEntee, Cali M., Cavalier, Alyssa N., Osburn, Shelby C., Burke, Samuel D., Grant, Randy A., Nerguizian, David, Lark, Daniel S., Link, Christopher D., LaRocca, Thomas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10186603/
https://www.ncbi.nlm.nih.gov/pubmed/36949552
http://dx.doi.org/10.1111/acel.13798
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author Wahl, Devin
Smith, Meghan E.
McEntee, Cali M.
Cavalier, Alyssa N.
Osburn, Shelby C.
Burke, Samuel D.
Grant, Randy A.
Nerguizian, David
Lark, Daniel S.
Link, Christopher D.
LaRocca, Thomas J.
author_facet Wahl, Devin
Smith, Meghan E.
McEntee, Cali M.
Cavalier, Alyssa N.
Osburn, Shelby C.
Burke, Samuel D.
Grant, Randy A.
Nerguizian, David
Lark, Daniel S.
Link, Christopher D.
LaRocca, Thomas J.
author_sort Wahl, Devin
collection PubMed
description 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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spelling pubmed-101866032023-05-17 The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction Wahl, Devin Smith, Meghan E. McEntee, Cali M. Cavalier, Alyssa N. Osburn, Shelby C. Burke, Samuel D. Grant, Randy A. Nerguizian, David Lark, Daniel S. Link, Christopher D. LaRocca, Thomas J. Aging Cell Research Articles 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. John Wiley and Sons Inc. 2023-03-22 /pmc/articles/PMC10186603/ /pubmed/36949552 http://dx.doi.org/10.1111/acel.13798 Text en © 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Wahl, Devin
Smith, Meghan E.
McEntee, Cali M.
Cavalier, Alyssa N.
Osburn, Shelby C.
Burke, Samuel D.
Grant, Randy A.
Nerguizian, David
Lark, Daniel S.
Link, Christopher D.
LaRocca, Thomas J.
The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title_full The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title_fullStr The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title_full_unstemmed The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title_short The reverse transcriptase inhibitor 3TC protects against age‐related cognitive dysfunction
title_sort reverse transcriptase inhibitor 3tc protects against age‐related cognitive dysfunction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10186603/
https://www.ncbi.nlm.nih.gov/pubmed/36949552
http://dx.doi.org/10.1111/acel.13798
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