Effects of age and dietary methionine restriction on cognitive and behavioural phenotypes in the rTg4510 model of frontotemporal dementia

Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of decreased brain glucose metabolism and insulin resistance in patients with dementia. Given the rising prevalence of age-related diseases, lifestyle adjustments and nutritional interventions are gaining interest. Dietary methionine restriction (MR) is a nutritional intervention that enhances insulin sensitivity and delays ageing-associated metabolic alterations. Since the potential impact of MR on neurodegenerative diseases like dementia is not fully understood, we here examined the metabolic and behavioural phenotypes of a murine tauopathy model (rTg4510), which overexpresses human P301L mutated tau, and assessed the impact of an 8-week dietary MR. The rTg4510 mice and wild type (WT) littermates were assessed at 6 and 12 months of age. While rTg4510 mice displayed progressive behavioural and motor impairments at 6 and 12 months of age, MR led to significant benefits in the aged 12-month-old cohort, improving motor coordination and learning, short-term memory, and social recognition. These effects were accompanied by increased glycolysis in the hippocampus and higher FGF21 levels in the cortex. These benefits occurred in the absence of alterations in glucose metabolism/adiposity in this model. Overall, our results support the positive impact of MR on rTg4510 mice, suggesting this as a potential therapeutic intervention to delay and/or improve the progression in tau-related disease.