The Impact of a High Fat Diet on AD‐risk Associated Genes in a Mouse Model of Alzheimer’s Disease

Abstract

AbstractBackgroundOver 80% of individuals with AD have a co‐morbid metabolic disease, defined as obesity, glucose intolerance, or diabetes. Both metabolic disease and a HF diet cause the release of inflammatory factors, increases AD risk, and alters the expression of hippocampal microvascular genes. Work has increased in identifying specific networks and the genes that drive these networks in AD. We hypothesize that AD causes baseline changes in a specific cluster of genes and when a HF diet is introduced, it further drives alterations of a sub‐population of genes to drive the worsening of AD pathology.MethodMale wild type (WT) and AppNL‐F knock‐in mice were given a low fat (LF; 10% fat) or high fat (HF; 60% fat; metabolic disease model) diet for 1 month. Weekly weights and end of study visceral fat weight were taken. The hippocampus was rapidly extracted and flash frozen for bulk RNA sequencing and differential gene expression analysis.ResultOn an LF diet, AppNL‐F mice had a greater body weight gain and greater visceral fat compared to WT controls. HF diet increased body weight and visceral fat in WT mice. There was surprisingly no difference between AppNL‐F mice on a LF diet and HF diet in body weight gain and visceral fat. There were 760 significant hippocampal gene alterations between AD and WT mice. Within the WT controls on a LF vs HF diet, there were 213 gene alterations and within the AD model on a LF vs HF diet, there were 31 gene alterations.ConclusionAppNL‐F mice on both a LF and HF diet gained equivalent amounts of weight, displaying an altered metabolic profile due to AD alone. While AD alone caused most of the gene alterations, a HF diet further drove alterations in a subset of genes. This work increases our understanding of the contribution of a HF diet to metabolic disease and alterations in AD‐risk associated hippocampal genes to uncover potential modifiable targets. We are currently examining specific clusters of genes and how they are linked to AD pathology, increased inflammation, and vascular dysfunction, and sequencing hippocampal samples from female mice to examine sex differences.