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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00843

Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

Kylie Kavanagh1,  Stephen M. Day1, Morgan C. Pait1, William R. Moritz2, Christopher B. Newgard3, Olga Ilkayeva3, Donald A. McClain1 and  Shannon L. Macauley1*
  • 1Wake Forest School of Medicine, United States
  • 2Washington University in St. Louis, United States
  • 3Duke University, United States

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a 2-4 fold increased risk for developing Alzheimer’s disease (AD), however the exact mechanisms linking the two disease is 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 sabeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to pre-diabetic 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 Aβ40 and CSF Aβ42 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 Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 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.

Keywords: Metabolomics, type 2 diabetes, Alzheiemr's disease, amyloid-beta, CSF, Amino Acids, Acylcarnitine, Hyperglycemia

Received: 07 Jun 2019; Accepted: 26 Jul 2019.

Copyright: © 2019 Kavanagh, Day, Pait, Moritz, Newgard, Ilkayeva, McClain and Macauley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Shannon L. Macauley, Wake Forest School of Medicine, Winston-Salem, 27157, North Carolina, United States, smacaule@wakehealth.edu