Brain-wide insulin resistance, tau phosphorylation changes, and hippocampal neprilysin and amyloid-β alterations in a monkey model of type 1 diabetes

Abstract

Epidemiological findings suggest that diabetic individuals are at a greater risk for developing Alzheimer’s disease (AD). To examine the mechanisms by which diabetes mellitus (DM)maycontribute to AD pathology in humans, we examined brain tissue from streptozotocintreated type 1 diabetic adult male vervet monkeys receiving twice-daily exogenous insulin injections for 8 –20 weeks. We found greater inhibitory phosphorylation of insulin receptor substrate 1 in each brain region examined of the diabetic monkeys when compared with controls, consistent with a pattern of brain insulin resistance that is similar to that reported in the human AD brain. Additionally, a widespread increase in phosphorylated tau was seen, including brain areas vulnerable in AD, as well as relatively spared structures, such as the cerebellum. An increase in active ERK1/2 was also detected, consistent with DM leading to changes in tau-kinase activity broadly within the brain. In contrast to these widespread changes, we found an increase in soluble amyloid-β (Aβ) levels that was restricted to the temporal lobe, with the greatest increase seen in the hippocampus. Consistent with this localized Aβ increase, a hippocampus-restricted decrease in the protein and mRNA for the Aβ-degrading enzyme neprilysin (NEP) was found, whereas various Aβ-clearing and -degrading proteins were unchanged. Thus, we document multiple biochemical changes in the insulin-controlledDMmonkey brain that can link DM with the risk of developing AD, including dysregulation of the insulin-signaling pathway, changes in tau phosphorylation, and a decrease in NEP expression in the hippocampus that is coupled with a localized increase in Aβ.