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Type-2-diabetes alters CSF but not plasma metabolomic and ad risk profiles in vervet monkeys

Citation

Kavanagh, K and Day, SM and Pait, MC and Mortiz, WR and Newgard, CB and Ilkayeva, O and Mcclain, DA and Macauley, SL, Type-2-diabetes alters CSF but not plasma metabolomic and ad risk profiles in vervet monkeys, Frontiers in Neuroscience, 13 pp. 1-10. ISSN 1662-4548 (2019) [Refereed Article]


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Copyright Statement

Copyright 2019 Kavanagh, Day, Pait, Mortiz, Newgard, Ilkayeva, Mcclain and Macauley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)

DOI: doi:10.3389/fnins.2019.00843

Abstract

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ 40 and CSF Aβ 42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ 40 and CSF Aβ 42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ 40 and CSF Aβ 42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

Item Details

Item Type:Refereed Article
Keywords:Alzheimer’s disease, CSF, acylcarnitine, amino acids, amyloid-beta, hyperglycemia, metabolomics, type 2 diabetes
Research Division:Biomedical and Clinical Sciences
Research Group:Medical biochemistry and metabolomics
Research Field:Medical biochemistry - amino acids and metabolites
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Kavanagh, K (Associate Professor Kylie Kavanagh)
ID Code:144349
Year Published:2019
Web of Science® Times Cited:5
Deposited By:Medicine
Deposited On:2021-05-14
Last Modified:2021-06-23
Downloads:3 View Download Statistics

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