Biology subjects

Rigby, M. J.

Publications and source records attributed to Rigby, M. J..

3 recordsLinked to original sources

bioRxiv2025

Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimers disease in 3xTg mice

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 Alzheimers 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.

physiology↗

bioRxiv2024

Fasting is required for many of the benefits of calorie restriction in the 3xTg mouse model of Alzheimer&aposs disease

Caloric restriction (CR) is a widely recognized geroprotective intervention that slows or prevents Alzheimers disease (AD) in animal models. CR is typically implemented via feeding mice a single meal per day; as CR mice rapidly consume their food, they are subject to a prolonged fast between meals. While CR has been shown to improve metabolic and cognitive functions and suppress pathological markers in AD mouse models, the specific contributions of fasting versus calorie reduction remains unclear. Here, we investigated the contribution of fasting and energy restriction to the beneficial effects of CR on AD progression. To test this, we placed 6-month-old 3xTg mice on one of several diet regimens, allowing us to dissect the effects of calories and fasting on metabolism, AD pathology, and cognition. We find that energy restriction alone, without fasting, was sufficient to improve glucose tolerance and reduce adiposity in both sexes, and to reduce A{beta} plaques and improve aspects of cognitive performance in females. However, we find that a prolonged fast between meals is necessary for many of the benefits of CR, including improved insulin sensitivity, reduced phosphorylation of tau, decreased neuroinflammation, inhibition of mTORC1 signaling, and activation of autophagy, as well as for the full cognitive benefits of CR. Finally, we find that fasting is essential for the benefits of CR on survival in male 3xTg mice. Overall, our results demonstrate that fasting is required for the full benefits of a CR diet on the development and progression of AD in 3xTg mice, and suggest that both when and how much we eat influences the development and progress of AD.

physiology↗

bioRxiv2024

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease

Age is the greatest risk factor for Alzheimers disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.

physiology↗