Role of Insulin Receptor Substrate-2 Expression in Alzheimer's Disease Development

The Alzheimer Research Initiative (Alzheimer Forschung Initiative e. V.) funded research at the University Hospital of Cologne between 2008 and 2010, focusing on the role of insulin receptor substrate-2 (IRS2) expression in the development of Alzheimer's disease.

The project was motivated by clinical studies noting a link between type 2 diabetes and Alzheimer's disease. Researchers explored the hypothesis that Alzheimer's could be a "diabetes of the brain," where insulin signaling pathways in the brain become dysfunctional. Previous findings had indicated reduced levels of insulin receptors and associated signaling proteins in the brains of Alzheimer's patients, which correlated with disease severity.

Using genetically engineered mouse models, the study aimed to determine if increased IRS2 expression in nerve cells exacerbated or mitigated Alzheimer's-like pathology. The project successfully generated mice overexpressing IRS2 in neurons. These mice were slated for cross-breeding with Alzheimer's models (Tg2576) to investigate these effects, a process ongoing at the project's conclusion.

Initial analyses of mice overexpressing IRS2 without Alzheimer's pathology revealed that it did not improve learning performance but rather worsened it. These mice also exhibited reduced locomotor activity. The research also established neuronal cell cultures to examine the role of IRS proteins in neuronal survival under stress, such as high glucose concentrations typical of diabetes.

The research project, led by Dr. med. Markus Schubert at the University Hospital of Cologne, received €60,440 in funding for research into the causes of the disease. The project's findings were documented in its final report.