Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

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

doi:10.1002/advs.202515220

Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

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 AttieLuigi Puglielli, Cholsoon Jang, Dudley W Lamming

Research output: Contribution to journal › Article › peer-review

1 Citation (SciVal)

Abstract

Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.

Original language	English
Article number	e15220
Journal	Advanced Science
Early online date	12 Mar 2026
DOIs	https://doi.org/10.1002/advs.202515220
Publication status	E-pub ahead of print - 12 Mar 2026

Bibliographical note

Publisher Copyright:
© 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Data Availability Statement

RNA-sequencing data have been deposited with the Gene Expression Omnibus and are available under accession number GSE299928. The authors declare that source data supporting the findings of this study are available within the paper and its supplementary information and Source Data files. An interactive exploration of all the transcriptomic and phenotypic data generated in this study is available via a web-based application at: https://connect.doit.wisc.edu/dlamming_BCAA_AD/

Acknowledgements

We thank all the members of the Lamming lab for their feedback and Brian Yandell for assistance with web hosting. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG081482, AG084156, AG085898, and AG094153), the NIDDK (DK125859), by a grant from the Alzheimer's Association (23AARG-1029665), and by startup funds from UW-Madison. RB was supported in part by F31AG081115 and is a UW Distinguished Research Fellow; support for this research was provided by the University of Wisconsin-Madison Office of the Vice Chancellor for Research with funding from the Wisconsin Alumni Research Foundation. CLG was supported in part by Dalio Philanthropies, a Glenn Foundation for Medical Research Postdoctoral Fellowship, and by grant HF-AGE AGE-009 from the Hevolution Foundation to CLG. MFC was supported in part by F31AG082504. CYY was supported in part by a NIA F32 postdoctoral fellowship (F32AG077916), a NIA K99/R00 award (K99AG084921), and a Research Enrichment Component Postdoctoral Scholarship from the Wisconsin Alzheimer's Disease Research Center (P30-AG062715). The Puglielli lab is supported in part by the NINDS (NS094154), the NIGMS (GM148487) and the NIA (AG078794). CJ is supported in part by the NIAAA (R01AA029124). ADA is supported by the NIH (RC2DK125961). The Harris lab is supported by the NIA (R03AG088813), Wisconsin Alzheimer's Disease Research Center (P30-AG062715), UW Department of Surgery, School of Medicine and Public Health, Wisconsin Alumni Research Fund, and the Office of the Vice Chancellor for Research. Additionally, DAH is a UW Madison Vilas Early Career Investigator. The authors thank the University of Wisconsin Carbone Cancer Center Experimental Animal Pathology Laboratory supported by P30 CA014520, for use of its facilities and services. DAH, AA, LP, and DWL are members of the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, and this work was supported in part by facilities and resources within the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, P30 AG092586. The Lamming lab was supported in part by the U.S. Department of Veterans Affairs (I01-BX004031 and IS1-BX005524), 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.

Funding

We thank all the members of the Lamming lab for their feedback and Brian Yandell for assistance with web hosting. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG081482, AG084156, AG085898, and AG094153), the NIDDK (DK125859), by a grant from the Alzheimer's Association (23AARG‐1029665), and by startup funds from UW‐Madison. RB was supported in part by F31AG081115 and is a UW Distinguished Research Fellow; support for this research was provided by the University of Wisconsin‐Madison Office of the Vice Chancellor for Research with funding from the Wisconsin Alumni Research Foundation. CLG was supported in part by Dalio Philanthropies, a Glenn Foundation for Medical Research Postdoctoral Fellowship, and by grant HF‐AGE AGE‐009 from the Hevolution Foundation to CLG. MFC was supported in part by F31AG082504. CYY was supported in part by a NIA F32 postdoctoral fellowship (F32AG077916), a NIA K99/R00 award (K99AG084921), and a Research Enrichment Component Postdoctoral Scholarship from the Wisconsin Alzheimer's Disease Research Center (P30‐AG062715). The Puglielli lab is supported in part by the NINDS (NS094154), the NIGMS (GM148487) and the NIA (AG078794). CJ is supported in part by the NIAAA (R01AA029124). ADA is supported by the NIH (RC2DK125961). The Harris lab is supported by the NIA (R03AG088813), Wisconsin Alzheimer's Disease Research Center (P30‐AG062715), UW Department of Surgery, School of Medicine and Public Health, Wisconsin Alumni Research Fund, and the Office of the Vice Chancellor for Research. Additionally, DAH is a UW Madison Vilas Early Career Investigator. The authors thank the University of Wisconsin Carbone Cancer Center Experimental Animal Pathology Laboratory supported by P30 CA014520, for use of its facilities and services. DAH, AA, LP, and DWL are members of the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, and this work was supported in part by facilities and resources within the Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, P30 AG092586. The Lamming lab was supported in part by the U.S. Department of Veterans Affairs (I01‐BX004031 and IS1‐BX005524), 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.

Funders	Funder number
School of Medicine and Public Health, University of Wisconsin-Madison
William S. Middleton Memorial Veterans Hospital
University of Wisconsin-Madison
Wisconsin Alumni Research Foundation
Department of Surgery
Office of the Vice Chancellor for Research, University of Illinois at Chicago
Dalio Foundation
Glenn Foundation for Medical Research	HF‐AGE AGE‐009
U.S. Department of Veterans Affairs	I01‐BX004031, IS1‐BX005524
Wisconsin Alzheimer's Disease Research Center	P30‐AG062715
Nathan Shock Center, University of Alabama at Birmingham	P30 AG092586
National Institutes of Health	R03AG088813, RC2DK125961
National Institute of Diabetes and Digestive and Kidney Diseases	DK125859
Alzheimer's Association	23AARG‐1029665, F31AG081115
National Institute on Aging	AG084156, AG081482, AG094153, AG056771, AG062328, AG085898
Hevolution Foundation	F32AG077916, F31AG082504, K99AG084921
National Institute on Alcohol Abuse and Alcoholism	R01AA029124
National Institute of Neurological Disorders and Stroke	NS094154
National Institute of General Medical Sciences	GM148487, AG078794

Keywords

Alzheimer's disease
autophagy
branched chain amino acids
mTORC1

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Materials Science
General Engineering
General Physics and Astronomy

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Cite this

Babygirija, R., Green, C. L., Sonsalla, M. M., Le, I. M. F., Xiao, F., Yandell, S., Calubag, M. F., Trautman, M. E., Tobon, A., Matoska, R., Yeh, C.-Y., Opara, C. I., Grunow, I., Vertein, D., Schlorf, S., Knopf, B. A., Rigby, M. J., Harris, D. A., Keller, M. P., ... Lamming, D. W. (2026). Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice. Advanced Science, Article e15220. Advance online publication. https://doi.org/10.1002/advs.202515220

Babygirija, R, Green, CL, Sonsalla, MM, Le, IMF, Xiao, F, Yandell, S, Calubag, MF, Trautman, ME, Tobon, A, Matoska, R, Yeh, C-Y, Opara, CI, Grunow, I, Vertein, D, Schlorf, S, Knopf, BA, Rigby, MJ, Harris, DA, Keller, MP, Attie, AD, Puglielli, L, Jang, C & Lamming, DW 2026, 'Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice', Advanced Science. https://doi.org/10.1002/advs.202515220

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title = "Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice",

abstract = "Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.",

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author = "Reji Babygirija and Green, \{Cara L\} and Sonsalla, \{Michelle M\} and Le, \{Izabelle Marie F\} and Fan Xiao and Sarah Yandell and Calubag, \{Mariah F\} and Trautman, \{Michaela E\} and Anna Tobon and Ryan Matoska and Chung-Yang Yeh and Opara, \{Charles I\} and Isaac Grunow and Diana Vertein and Sophia Schlorf and Knopf, \{Bailey A\} and Rigby, \{Michael J\} and Harris, \{David A\} and Keller, \{Mark P\} and Attie, \{Alan D\} and Luigi Puglielli and Cholsoon Jang and Lamming, \{Dudley W\}",

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AU - Babygirija, Reji

AU - Green, Cara L

AU - Sonsalla, Michelle M

AU - Le, Izabelle Marie F

AU - Xiao, Fan

AU - Yandell, Sarah

AU - Calubag, Mariah F

AU - Trautman, Michaela E

AU - Tobon, Anna

AU - Matoska, Ryan

AU - Yeh, Chung-Yang

AU - Opara, Charles I

AU - Grunow, Isaac

AU - Vertein, Diana

AU - Schlorf, Sophia

AU - Knopf, Bailey A

AU - Rigby, Michael J

AU - Harris, David A

AU - Keller, Mark P

AU - Attie, Alan D

AU - Puglielli, Luigi

AU - Jang, Cholsoon

AU - Lamming, Dudley W

PY - 2026/3/12

Y1 - 2026/3/12

N2 - Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.

AB - Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.

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KW - autophagy

KW - branched chain amino acids

KW - mTORC1

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DO - 10.1002/advs.202515220

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ER -

Restriction of Individual Branched-Chain Amino Acids has Distinct Effects on the Development and Progression of Alzheimer's Disease in 3xTg Mice

Abstract

Bibliographical note

Data Availability Statement

Acknowledgements

Funding

Keywords

ASJC Scopus subject areas

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