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Evidence for brain glucose dysregulation in Alzheimer's disease.

ABSTRACT: INTRODUCTION:It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. METHODS:Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. RESULTS:Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. DISCUSSION:Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

SUBMITTER: An Y

PROVIDER: S-EPMC5866736 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Evidence for brain glucose dysregulation in Alzheimer's disease.

An Yang Y Varma Vijay R VR Varma Sudhir S Casanova Ramon R Dammer Eric E Pletnikova Olga O Chia Chee W CW Egan Josephine M JM Ferrucci Luigi L Troncoso Juan J Levey Allan I AI Lah James J Seyfried Nicholas T NT Legido-Quigley Cristina C O'Brien Richard R Thambisetty Madhav M

Alzheimer's & dementia : the journal of the Alzheimer's Association 20171019 3

<h4>Introduction</h4>It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis.<h4>Methods</h4>Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the rela ...[more]

PMID: 29055815

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Project description:Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer's disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing 'pre', 'peri' and 'post' onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.

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Evidence for brain glucose dysregulation in Alzheimer's disease.

Publications

Evidence for brain glucose dysregulation in Alzheimer's disease.

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