title: 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) 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.
  
  
  CONCLUSIONS
  Given that diabetes mellitus (DM) appears to increase the risk of developing Alzheimer's disease (AD), understanding the mechanisms by which DM promotes AD is important. We report that DM in a nonhuman primate brain leads to changes in the levels or posttranslational processing of proteins central to AD pathobiology, including tau, amyloid-β (Aβ), and the Aβ-degrading protease neprilysin. Additional evidence from this model suggests that alterations in brain insulin signaling occurred that are reminiscent of insulin signaling pathway changes seen in human AD. Thus, in an in vivo model highly relevant to humans, we show multiple alterations in the brain resulting from DM that are mechanistically linked to AD risk.
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, Departments of Psychiatry.
authors.forename: Jose
authors.initials: J
authors.lastname: Morales-Corraliza
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
authors.forename: Harrison
authors.initials: H
authors.lastname: Wong
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Mazzella
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, Departments of Psychiatry.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Che
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
authors.forename: Sang Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, Child and Adolescent Psychiatry, and.
authors.forename: Eva
authors.initials: E
authors.lastname: Petkova
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, and.
authors.forename: Janice D
authors.initials: JD
authors.lastname: Wagner
authors.affiliation: Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina 27268.
authors.forename: Scott E
authors.identifier: http://orcid.org/0000-0002-6987-1133
authors.initials: SE
authors.lastname: Hemby
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, Departments of Psychiatry, Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016.
authors.forename: Stephen D
authors.identifier: http://orcid.org/0000-0002-1797-4288
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, Departments of Psychiatry, mathews@nki.rfmh.org.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry; D002522:Chlorocebus aethiops; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D015260:Neprilysin
keywords: alzheimer's disease; diabetes; hippocampus; neprilysin; nonhuman primate; streptozotocin