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. Overall design: The impact of chronic elevated glucose levels on synapse loss was tested in homozygous AppNL-G-F/hMapt double knock-in (DKI) mouse model of Alzheimer's Diease. DKI mice on a sustained control diet, containing low sucorse, or high fat diet, were compared to wild type mice under going the same treatment. Mice in all groups were evaluated for behavioral deficits, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling.