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 and Dudley W. Lamming ()
Additional contact information
Reji Babygirija: University of Wisconsin-Madison
Michelle M. Sonsalla: University of Wisconsin-Madison
Jericha Mill: University of Wisconsin-Madison
Isabella James: University of Wisconsin-Madison
Jessica H. Han: University of Wisconsin-Madison
Cara L. Green: University of Wisconsin-Madison
Mariah F. Calubag: University of Wisconsin-Madison
Gina Wade: University of Wisconsin-Madison
Anna Tobon: University of Wisconsin-Madison
John Michael: University of Wisconsin-Madison
Michaela M. Trautman: University of Wisconsin-Madison
Ryan Matoska: University of Wisconsin-Madison
Chung-Yang Yeh: University of Wisconsin-Madison
Isaac Grunow: University of Wisconsin-Madison
Heidi H. Pak: University of Wisconsin-Madison
Michael J. Rigby: University of Wisconsin-Madison
Dominique A. Baldwin: University of Wisconsin-Madison
Natalie M. Niemi: Washington University School of Medicine in St. Louis
John M. Denu: University of Wisconsin-Madison
Luigi Puglielli: University of Wisconsin-Madison
Judith Simcox: University of Wisconsin-Madison
Dudley W. Lamming: University of Wisconsin-Madison

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49589-z

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