Restriction of Individual Branched‐Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice
Year: 2026
Type: article
Abstract: Dietary protein is a critical regulator of metabolic health and aging in diverse species. Recent discoveries have determined that many benefits of a low protein diet are the result of reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Intriguingly, each BCAA has distinct physiological and molecular effects, with restriction of isoleucine alone being sufficient to improve metabolic health and extend the lifespan of mice. While restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the impact of restricting each individual BCAA on the progression and development of AD is unknown. Here, we investigate the effect of restricting each individual BCAA on metabolic health, AD pathology, molecular signaling, and cognition in the 3xTg mouse model. We find that restriction of isoleucine and valine, but not leucine, promotes metabolic health. Restriction of each BCAA had distinct effects on AD pathology and molecular signaling, with transcriptomic analysis of the brain revealing both distinct and shared, and highly sex-specific, molecular impacts of restricting each BCAA. Restricting any of the three BCAAs improved short-term memory in males, with isoleucine restriction having the strongest effect, while restricting valine had the greatest cognitive benefits in females. We identify a set of significantly altered pathways strongly associated with reduced AD pathology and improved cognitive performance in males. Our findings suggest that restricting any of the BCAAs, particularly isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay the progression of AD.
Source: Advanced Science
Authors: Reji Babygirija, Cara L. Green, Michelle M. Sonsalla, Izabelle Marie F. Le, Fan Xiao, Sarah Yandell, Mariah F. Calubag, Michaela E. Trautman, Anna Tobon, Ryan Matoska, Chung‐Yang Yeh, Charles I. Opara, Isaac Grunow, Diana Vertein, Sophia Schlorf, Bailey A. Knopf, Michael J. Rigby, David A. Harris, Mark P. Keller, Alan D. Attie, Luigi Puglielli, Cholsoon Jang, Dudley W. Lamming
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Funders: Hevolution Foundation, U.S. Department of Veterans Affairs, Alzheimer's Association, Glenn Foundation for Medical Research, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G307440276, G3405018120, Dietary Interventions in Alzheimer’s Disease, Safer mTOR inhibition for human geroprotection, G42610423, G441436445, G4755141327, Comparative analysis of geroprotective interventions in established and novel mouse models of Alzheimer's disease, G5451514562, G5581438442, The regulation of health and longevity by branched-chain amino acids, The regulation of health and longevity by branched-chain amino acids, G6460484544, G6555710345, G6557196061, G6733044160, G7191816419, G7667824514, G7727581783, The regulation of health and longevity by branched-chain amino acids, G8464745751, G8513121114, Dietary regulation of the hepatic epigenome, Spastic paraplegia, neurodegeneration and autism: possible role for AT- 1/SLC33A1?, Creating a region- specific biomolecular atlas of the brain of Alzheimer’s disease, UW Comprehensive Cancer Center Support, Integrated Training For Physician-Scientists, Regulation of cellular senescence and metabolic health by dietary protein, The regulation of cancer and aging by methionine, Elucidating dietary fructose and alcohol interactions during liver cancer development, Integrating spatial transcriptomics and single cell RNA-sequencing to mechanistically define bariatric surgery's impact on Alzheimer's Disease, ATase1 and ATase2, proteostasis, and neurological diseases, Understanding the roles of prolonged fasting, calorie intake, and mTORC1 in the response to calorie restriction, Wisconsin Alzheimer's Disease Research Center, Investigating the Mechanistic Role of Dietary Protein in Aging and in Alzheimer's Disease, The Role of Prolonged Fasting in the Effects of Calorie Restriction on AD, Genetic Control of Metabolic Flux in Response to Diet
OpenAlex ID: W7135040904