Effects of a high-fat diet on cognition and brain distribution of intranasal insulin in E3 and E4 male and female mice

• Published in: Scientific reports Vol. 14; no. 1; pp. 18641 - 18
• Main Authors: Chaklai, Ariel, Rhea, Elizabeth M, O'Niel, Abigail, Babin, Alice, Weaver, Riley, Pemberton, Sarah, Banks, William A, Raber, Jacob
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.08.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Administration, Intranasal; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Brain - drug effects; Brain - metabolism; Cognition; Cognition & reasoning; Cognition - drug effects; Cognitive ability; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Environmental risk; Female; Females; Genotype & phenotype; Genotypes; High fat diet; Humans; Insulin; Insulin - metabolism; Intranasal insulin; Male; Mice; Mice, Transgenic; Neurodegenerative diseases; Nutrient deficiency; Risk factors; Sex; Cognition; Intranasal insulin; Apolipoprotein E; High-fat diet; Sex
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62053-8

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.