Does Chronic Expression of E4orf1 Improve Risk Factors and Cognition Decline in a Mouse Model of Obesity-Associated Alzheimer's Disease?

A key pathophysiological factor in obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) is insulin resistance. Insulin resistance, characterized by hyperglycemia and hyperinsulinemia, contributes to AD by raising AGEs, reducing synaptic plasticity, and enhancing oxidative stress and neuroinflammation. Despite obesity, the novel adenoviral protein E4orf1 enhances glycemic control and protects against the buildup of liver fat independent of insulin. We hypothesize that E4orf1 will slow the onset and progression of AD by improving insulin-related risk factors. In an older AD mouse model, we previously demonstrated that E4orf1 improves metabolic function and cognition. Here, we used an obesity-related transgenic mouse model of AD that expressed E4orf1 protein specifically in adipose tissue upon doxycycline feeding. Following baseline systemic (body weight, EchoMRI, oral glucose tolerance test, insulin, hemoglobin A1c) and behavioral (Y-maze and Morris Water Maze (MWM)) analyses, mice aged four to six months were given a 60% high-fat diet. These mice were classified as WT (n=20), APP/PS1 (n=14), and APP/PS1 expressing E4orf1 (n=11). A cohort of mice was sacrificed, and investigations were conducted again four months later. The remaining animals were sacrificed after the analyses were repeated eight months later. Western blot and RT-qPCR were used for molecular pathway analysis in the brain, liver, and adipose tissue. ELISA was used to assess biomarkers from plasma samples. Despite a high-fat diet, E4orf1 expression significantly decreased HbA1c, decreased endogenous insulin needs for glucose clearance, reduced body weight, and improved habituation and spatial memory in Y-Maze and MWM tests, even though APP/PS1 mice are prone to AD. E4orf1 downregulated the expression of genes involved in triglyceride synthesis, fatty acid transport, fat oxidation, and lipogenesis in the liver. It significantly upregulated genes linked to fatty acid transport, β-oxidation, and TG production in adipose tissue. E4orf1 had no distinct impact in the brain, indicating that it has no direct effect on the brain. However, as demonstrated by a decrease in plasma Aβ concentration, E4orf1 markedly decreased the peripheral amyloid beta (Aβ) burden. AD currently has no known cure, and the only treatments available are symptom management. E4orf1 can be a potential drug candidate to serve as an insulin-independent agent for AD.