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) may contribute to AD pathology in humans, we examined brain tissue from streptozotocin-treated 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-controlled DM monkey 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.
Pubmed ID: 27076423 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 30, 2023.NIH funded national research resource to provide biomedical research community with access to US born, known age, pedigreed, genomically sequenced, pathogen free Caribbean origin vervet monkeys also known as African green monkeys. Provides access to animals, extensive multisystem clinical phenotyping, sample and data repositories, expertise in use of nonhuman primate models for translational studies, serves as platform for training veterinarians and other professionals in biomedical research, husbandry, clinical care, and the colony behavioral management.
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