Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 15, Pages 4248-4258Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4640-14.2016
Keywords
alzheimer's disease; diabetes; hippocampus; neprilysin; nonhuman primate; streptozotocin
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Funding
- National Institute on Aging Pilot Project from the NYU Alzheimer's Disease Center [P30 AG008051]
- Alzheimer's Association [IIRG-12-237253]
- Juvenile Diabetes Research Foundation [7-2005-1152]
- monkey colony [RR019963/OD010965]
- [AG017617]
- [AG043375]
- [AG014449]
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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-beta (A beta) levels that was restricted to the temporal lobe, with the greatest increase seen in the hippocampus. Consistent with this localized A beta increase, a hippocampus-restricted decrease in the protein and mRNA for the A beta-degrading enzyme neprilysin (NEP) was found, whereas various A beta-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 A beta.
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