Panyard, DJ;
McKetney, J;
Deming, YK;
Morrow, AR;
Ennis, GE;
Jonaitis, EM;
Van Hulle, CA;
... Engelman, CD; + view all
(2023)
Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease.
Alzheimer's and Dementia
10.1002/alz.13130.
(In press).
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Abstract
INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P < 5.46 × 10−5) and 636 significant protein-biomarker associations (P < 6.07 × 10−6). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine–phosphorylated tau association.
| Type: | Article |
|---|---|
| Title: | Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/alz.13130 |
| Publisher version: | https://doi.org/10.1002/alz.13130 |
| Language: | English |
| Additional information: | © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
| Keywords: | Alzheimer's disease, acylcarnitines, amyloid, biomarkers, carbon metabolism, glucose metabolism, metabolism, metabolomics, multiomics, neurodegeneration, neuroinflammation, proteomics, tau |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171469 |
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