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

Nat Commun. 2024 Jun 18;15(1):5217. doi: 10.1038/s41467-024-49589-z.

Authors

Reji Babygirija^{1

2

3}, Michelle M Sonsalla^{1

2

4}, Jericha Mill⁵, Isabella James^{5

6}, Jessica H Han^{3

7}, Cara L Green^{1

2}, Mariah F Calubag^{1

2

3}, Gina Wade^{5

6}, Anna Tobon^{1

2}, John Michael^{1

2}, Michaela M Trautman^{1

2

8}, Ryan Matoska^{1

2}, Chung-Yang Yeh^{1

2}, Isaac Grunow^{1

2}, Heidi H Pak^{1

2

8}, Michael J Rigby^{9

10}, Dominique A Baldwin^{5

11}, Natalie M Niemi¹², John M Denu^{7

8}, Luigi Puglielli^{1

2}, Judith Simcox^{3

5

6

8

11}, Dudley W Lamming^{13

14

15

16

17}

Affiliations

¹ Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
² William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
³ Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
⁴ Comparative Biomedical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
⁶ Integrated Program in Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
⁷ Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
⁸ Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA.
⁹ Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
¹⁰ Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, 53705, USA.
¹¹ Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI, 53706, USA.
¹² Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
¹³ Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu.
¹⁴ William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. dlamming@medicine.wisc.edu.
¹⁵ Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu.
¹⁶ Comparative Biomedical Sciences, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu.
¹⁷ Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu.

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.

MeSH terms

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

Substances

Mechanistic Target of Rapamycin Complex 1
Sphingolipids

Abstract

MeSH terms

Substances

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