Altered gene expression of amyloid precursor protein in the adipose tissue and brain of obese mice fed with long-term high-fat diet and streptozotocin-induced diabetic mice

Mid-life obesity is associated with increased risk of Alzheimer's disease (AD). Amyloid precursor protein (APP) and its processing are centrally involved in the etiology of AD. Our previous studies demonstrated that human APP is expressed in adipocytes, up-regulated with obesity, and correlated with adipokine expression. This study was to determine whether APP expression is also dysregulated in mouse models of obesity and diabetes. Six-week-old C57BL/6 mice were fed normal or high-fat diets (HFD) until 16, 26, 36, 47, or 77 weeks of age. We measured gene expression of APP and adipokines, levels of glucose and insulin, and area under the glucose curve (AUC(glucose)) during the glucose tolerance test. Using quantitative real-time polymerase chain reaction (PCR), we demonstrated that APP expression in subcutaneous adipose tissue (SAT) significantly increased in all HFD mice groups, and that it correlated with the levels of AUCglucose, insulin, and expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and chemokine (C-C motif) ligand 2 (CCL2) genes. Thiazolidinedione treatment significantly reduced plasma insulin levels and APP expression in SAT and epididymal adipose tissue. APP expression in the SAT and brain also decreased significantly in streptozotocin-induced diabetic mice, indicating an important role of insulin in the regulation of APP gene expression. These results demonstrate that adipose tissue APP expression is increased with obesity and regulated by insulin levels, suggesting that the regulation and role of APP are similar in humans and mice. Insights into APP regulation and processing in the adipose tissue may improve our understanding of obesity-related adipose tissue inflammation and the increased risk of AD in obese individuals.