Systemic and central nervous system metabolic alterations in Alzheimer's disease

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_901648E242CF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Systemic and central nervous system metabolic alterations in Alzheimer's disease
Journal
Alzheimer's Research & Therapy
Author(s)
van der Velpen Vera (co-first), Teav Tony (co-last), Gallart-Ayala Héctor, Mehl Florence, Konz Ioana, Clark Christopher, Oikonomidi Aikaterini, Peyratout Gwendoline, Henry Hugues, Delorenzi Mauro, Ivanisevic Julijana (co-last), Popp Julius (co-last)
ISSN
1758-9193
Publication state
Published
Issued date
12/2019
Peer-reviewed
Oui
Volume
11
Number
1
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration.
In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway.
Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1-42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1-42, or tau and phosphorylated Tau-181.
This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.
Keywords
Cognitive Neuroscience, Neurology, Clinical Neurology
Pubmed
Web of science
Open Access
Yes
Funding(s)
Swiss National Science Foundation
Create date
09/12/2019 15:52
Last modification date
08/02/2024 7:16
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