Background

Obesity, and type 2 diabetes are closely linked with Alzheimer's disease(AD) in which amyloid β plaques and hyper-phosphorylated tau accumulate in the brain with associated cognitive decline, dementia and eventual death. Human adenovirus36 (Ad36) and its E4orf1 protein improve glycemic control independent of insulin action. In a mouse model predisposed to impaired glycemic control and AD(APPswe mice, Tg2576 line), we observed that Ad36 improves glycemic control and ameliorates cognitive decline.Here, we investigated the ability of Ad36 to reduce amyloid β levels and improve morphology of neurons in the brain along with increased expression of metabolic genes in the liver of these mice. Next, we determined the ability of E4orf1 to improve glycemic control in the APP/PSEN1 mouse model of AD.

Methods

Experiment 1:3-month old APPswe mice were divided into two weight-matched groups, Ad36 infected(Ad36) or mock infected(CON). Twenty-four weeks post infection mice were sacrificed.Experiment 2: APP/PSEN1 mice were crossed with transgenic mice expressing E4orf1 to obtain APP/PS1-E4orf1 triple transgenic mice. Glycemic control was determined by measuring glucose and insulin during a glucose tolerance test (GTT) at 2-months of age.

Results

Sandwich ELISA analysis of cerebral cortex tissue lysate showed reduced level of Aβ 42(p=0.0007) in AD36 mice vs CON. Golgi-cox staining analysis revealed that dendritic spines are significantly increased in Ad36 infected mice relative to CON mice. Ad36 also protected liver from fatty acid transport.APP/PSEN1 mice with E4orf1 expression significantly improved glycemic control(AUC; p=0.01) compared with APP/PSEN1 mice without E4orf1 expression.

Conclusions

In transgenic mice prone to AD, Ad36 and its E4orf1 protein improve glycemic control, expression of metabolic genes in the liver, lower Aβ levels and morphology of neurons in the brain. Additional and long-term research is needed to determine if Ad36E4orf1 approaches may help in improving the pathology of AD.