Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease

Reji Babygirija; Michelle M Sonsalla; Jericha Mill; Isabella James; Jessica H Han; Cara L Green; Mariah F Calubag; Gina Wade; Anna Tobon; John Michael; Michaela M Trautman; Ryan Matoska; Chung-Yang Yeh; Isaac Grunow; Heidi H Pak; Michael J Rigby; Dominique A Baldwin; Natalie M Niemi; John M Denu; Luigi Puglielli; Judith Simcox; Dudley W Lamming

doi:10.1038/s41467-024-49589-z

Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease

Reji Babygirija
, Michelle M Sonsalla
, Jericha Mill
, Isabella James
, Jessica H Han
, Cara L Green
, Mariah F Calubag
, Gina Wade
, Anna Tobon
, John Michael
, Michaela M Trautman
, Ryan Matoska
, Chung-Yang Yeh
, Isaac Grunow
, Heidi H Pak
, Michael J Rigby
, Dominique A Baldwin
, Natalie M Niemi
, John M Denu
, Luigi Puglielli

Judith Simcox, Dudley W Lamming

Department for Health

University of Wisconsin-Madison
Department of Medicine
William S. Middleton Memorial Veterans Hospital
Washington University in St. Louis

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

16 Citations (SciVal)

Abstract

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Original language	English
Pages (from-to)	5217
Number of pages	20
Journal	Nature Communications
Volume	15
Issue number	1
Early online date	18 Jun 2024
DOIs	https://doi.org/10.1038/s41467-024-49589-z
Publication status	Published - 18 Jun 2024

Bibliographical note

Acknowledgements

We thank all members of the Lamming lab for their feedback.

Funding

The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG061635, AG081482, and AG084156), 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. M.M.S. was supported in part by a Supplement to Promote Diversity in Health‐Related Research RF1AG056771-06S1. M.M.T. was supported in part by a Supplement to Promote Diversity in Health‐Related Research R01AG062328-03S1. C.L.G. 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. M.F.C. was supported in part by F31 AG082504. C.- Y.Y. was supported in part by a training grant from the NIA (T32 AG000213) and by F32 AG077916. H.H.P. was supported in part by F31AG066311. The Niemi lab is supported by the NIGMS (R35GM151130). The Puglielli lab is supported in part by the NINDS (NS094154), the NIGMS (GM148487) and the NIA (AG078794). The Simcox lab is supported in part by the NIDDK (R01DK133479), a pilot grant to JS from the Diabetes Research Center at Washington University, P30DK020579, and a UW BIRCWH Scholars Program award to J.S. (K12HD101368). J.S. is a HHMI Freeman Hrabowski Scholar and is an American Federation for Aging Research grant recipient. 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.

Keywords

Animals
Alzheimer Disease/pathology
Disease Models, Animal
Female
Mice, Transgenic
Male
Mice
Disease Progression
Brain/metabolism
Diet, Protein-Restricted
Humans
Mechanistic Target of Rapamycin Complex 1/metabolism
Autophagy
Glucose Intolerance/metabolism
Sphingolipids/metabolism
Cognition
Mice, Inbred C57BL

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10.1038/s41467-024-49589-zLicence: CC BY

Cite this

Babygirija, R., Sonsalla, M. M., Mill, J., James, I., Han, J. H., Green, C. L., Calubag, M. F., Wade, G., Tobon, A., Michael, J., Trautman, M. M., Matoska, R., Yeh, C.-Y., Grunow, I., Pak, H. H., Rigby, M. J., Baldwin, D. A., Niemi, N. M., Denu, J. M., ... Lamming, D. W. (2024). Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease. Nature Communications, 15(1), 5217. https://doi.org/10.1038/s41467-024-49589-z

Babygirija, R, Sonsalla, MM, Mill, J, James, I, Han, JH, Green, CL, Calubag, MF, Wade, G, Tobon, A, Michael, J, Trautman, MM, Matoska, R, Yeh, C-Y, Grunow, I, Pak, HH, Rigby, MJ, Baldwin, DA, Niemi, NM, Denu, JM, Puglielli, L, Simcox, J & Lamming, DW 2024, 'Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease', Nature Communications, vol. 15, no. 1, pp. 5217. https://doi.org/10.1038/s41467-024-49589-z

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AU - Green, Cara L

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AU - Matoska, Ryan

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AU - Rigby, Michael J

AU - Baldwin, Dominique A

AU - Niemi, Natalie M

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Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease

Abstract

Bibliographical note

Acknowledgements

Funding

Keywords

Access to Document

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Cite this