Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer’s knock-in mouse phenotypes

Clinically, patients with diabetes have a higher risk of suffering from Alzheimer's disease (AD), with increased severity of cognitive decline upon disease onset. Several studies have reported on the metabolic impact of chronic hyperglycemia using various mouse models of AD, with varying results and behavioral outcomes. Furthermore, the underlying cellular mechanisms driving any observable increases in cognitive impairments remain unclear. In this study, we induced either Type-1 (streptozotocin, STZ) or Type-2 (chronic high-fat diet, HFD) diabetes on either wild type or a double knock-in AD mouse model. We found that there was no observable difference in behavioral defect between AD and AD mice with STZ-induced diabetes. However, AD mice on a chronic high-fat diet displayed increased impairments in memory and learning. Histological and transcriptomic analysis of these mice revealed an increase in glial-mediated synapse due to an altered metabolic state of microglia.