EARLY- AND LATE-ONSET DIETARY INTERVENTIONS MODULATE COGNITIVE AND METABOLIC DYSFUNCTION IN A TDP-43 PROTEINOPATHY MOUSE MODEL

TDP-43 proteinopathies are associated with progressive cognitive, motor, and metabolic impairments, and effective disease-modifying treatments are currently lacking. Increasing evidence suggests that dietary interventions can influence brain function and modify the course of neurodegenerative diseases. Here, we investigated the effects of dietary interventions applied at different ages in a TDP-43 M323K mouse model. Male and female wild-type and homozygous mutant mice were subjected either to caloric restriction (70%, CR) or to a high-fat diet (HFD). Dietary interventions were initiated at an early stage (6 weeks) or at a later stage (7 months), until mice reach 12 months of age, corresponding to lifelog preventing or a late adult intervention paradigm respectively. Cognitive function was assessed longitudinally every three months to monitor disease progression, and body weight was recorded throughout the study to confirm the effectiveness of dietary manipulation. Early dietary interventions significantly influenced the progression of cognitive and metabolic alterations in TDP-43 M323K mice. Caloric restriction preserved cognitive performance and, in some cases, resulted in functional improvements, whereas HFD exacerbated cognitive deficits in both mutant and wild-type animals. When interventions were initiated at later stages, after cognitive decline was already evident, caloric restriction preserved cognitive function but did not reverse established impairments. In contrast, the detrimental cognitive effects of HFD persisted, similar to those observed following early intervention. Overall, these findings demonstrate that dietary interventions can modulate cognitive outcomes when applied at both early and later stages of TDP-43 proteinopathy, to influence disease progression and functional outcomes in neurodegenerative disorders.