Abstract
Alzheimer’s disease (AD) is an age-associated neurodegenerative disease. As the population ages, the increasing prevalence of AD threatens massive healthcare costs in the coming decades. Unfortunately, traditional drug development efforts for AD have proven largely unsuccessful. A geroscience approach to AD suggests that since aging is the main driver of AD, targeting aging itself may be an effective way to prevent or treat AD. Here, we discuss the effectiveness of geroprotective interventions on AD pathology and cognition in the widely utilized triple-transgenic mouse model of AD (3xTg-AD) which develops both β-amyloid and tau pathologies characteristic of human AD, as well as cognitive deficits. We discuss the beneficial impacts of calorie restriction (CR), the gold standard for geroprotective interventions, and the effects of other dietary interventions including protein restriction. We also discuss the promising preclinical results of geroprotective pharmaceuticals, including rapamycin and medications for type 2 diabetes. Though these interventions and treatments have beneficial effects in the 3xTg-AD model, there is no guarantee that they will be as effective in humans, and we discuss the need to examine these interventions in additional animal models as well as the urgent need to test if some of these approaches can be translated from the lab to the bedside for the treatment of humans with AD.
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Acknowledgements
We would like to thank all members of the Lamming lab for their valuable insights and comments.
Funding
The Lamming Laboratory is supported in part by the NIH/National Institute on Aging (AG056771, AG062328 and AG061635 to D.W.L.), NIH/NIDDK (DK125859) and startup funds from the University of Wisconsin-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. M.M.S. was supported in part by a Research Supplement to Promote Diversity in Health-Related Research (3RF1AG056771-06S1). The Lamming laboratory is supported in part by the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government.
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D.W.L has received funding from, and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.
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Sonsalla, M.M., Lamming, D.W. Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease. GeroScience 45, 1343–1381 (2023). https://doi.org/10.1007/s11357-023-00782-w
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DOI: https://doi.org/10.1007/s11357-023-00782-w