An Evaluation of Alzheimer\u27s Disease-related Pathology in Two Different Models of Diabetes in Immune-challenged Mice

Obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome are related disorders with wide-ranging and devastating effects that can be observed throughout the body. One important and understudied organ of damage is the brain. Clinical and epidemiological studies have found that T2DM, and more specifically hyperinsulinemia, significantly increases the risk of cognitive decline and increases the likelihood of Alzheimer’s disease (AD) and other forms of dementia in the elderly. Insulin has slightly different functions in the peripheral body than in the central nervous system and the dysregulation of these functions may contribute to the onset and progression of late-life neurodegenerative disease. These experiments were designed to investigate cognitive function and AD-related disease pathology in two different models of diabetes, one model resulting from a diabetogenic compound that selectively targets insulin-producing pancreatic β-cells and the other model based on diet-induced obesity. Additionally, these diabetic models were combined with a genetic mouse model of inflammation to explore the compounding effects of multiple AD risk factors. We found that diabetic-status, regardless of whether it was drug- or diet-induced, resulted in profound impairments in learning and memory and subtle alterations to AD-related histopathology within the hippocampus. Additionally, impairments were most dramatic in male mice; whereas females appeared to be more resistant to metabolic disturbances