Reduction of Glycolysis Intermediate Concentrations in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

Bergau, Nick; Maul, Stephan; Rujescu, Dan; Simm, Andreas; Santos, Anne Navarrete

doi:10.3389/fnins.2019.00871

Cited by 30 publications

(27 citation statements)

References 20 publications

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“…Specifically, glycolysis has been extensively described for its essential roles in brain development and fast-occurring neuronal activities such as ion transport in neurotransmission. Despite its essential neural functions, glycolysis in the context of AD has not been explored much until recently ( Bergau et al, 2019 ; Butterfield and Halliwell, 2019 ; Theurey et al, 2019 ; Yan et al, 2020 ). Several clinical studies have indicated the involvement of glycolytic dysfunction in the development of AD pathologies ( Vlassenko et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Another clinical study that analyzed 122 metabolites in the CSF of AD and non-AD subjects showed that only intermediates of glycolysis, such as dihydroxyacetone phosphate (DHAP) and phosphoenolpyruvate (PEP), were significantly decreased in AD patients. The reduction of these glycolytic intermediates also exhibited positive correlation with Aβ 1 – 42 and Aβ 1 – 42 /Aβ 1 – 40 ( Bergau et al, 2019 ). A very recent study also reported that astrocytic glycolysis-derived L-serine exhibited a significant decrease in 3xTg-AD mice indicating a reduced glycolytic flux that led to impaired synaptic plasticity and memory ( Le Douce et al, 2020 ).…”

Section: Glycolysis In Admentioning

confidence: 97%

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Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021

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Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Glycolysis In Admentioning

confidence: 97%

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021

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“…In addition, cysteine has been identified as one of the 27 CSF metabolites distinguishable in different types of brain tumors [25]. Glucose levels in CSF are also demonstrated to be decreased in patients with Alzheimer's disease [26]. However, these studies have rarely described control of the postprandial state.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma

Saito

Hattori

Andou³

et al. 2020

Metabolites

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Cerebrospinal fluid (CSF) metabolites reflect biochemical diffusion/export from the brain and possibly serve as biomarkers related to brain disease severity, pathophysiology, and therapeutic efficacy/toxicity. Metabolomic studies using blood matrices have demonstrated interindividual and preanalytical variation of blood metabolites, whereas those of CSF metabolites remain unclear. In this study, we aimed to delineate the postprandial effects on CSF metabolites because fasting of patients with brain-related disorders is challenging. We collected pre- and postprandial (1.5, 3, and 6 h) plasma and CSF from nine healthy subjects. Using a mass-spectrometry-based global metabolomics approach, 150 and 130 hydrophilic metabolites and 263 and 340 lipids were detected in CSF and plasma, respectively. Principal component analysis of CSF hydrophilic metabolites and lipids primarily classified individual subjects at any time point, suggesting that the postprandial effects had a lower impact than interindividual variations on CSF metabolites. Individually, less than 10% of the CSF metabolites were putatively altered by postprandial effects (with either significant differences or over 2-fold changes, but not both) at any time point. Thus, global CSF metabolite levels are not directly associated with food intake, and except for several putatively altered CSF metabolites, postprandial effects are not a major concern when applying CSF metabolomics to screen biomarkers.

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“…18 and dementia have a left-lateralized rCMRgl decline (Weise et al, 2018). Another study reported a reduction of several glycolysis intermediates in CSF of AD patients compared with controls (Bergau et al, 2019). A recent study with fluorescence lifetime imaging microscopy (FLIM) imaging of primary neurons from transgenic AD mouse showed that these have reduced mitochondrial and cytosolic NAD(P)H, which suggest an impairment in glycolytic flux in these AD neurons (Theurey et al, 2019).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Glucose, glycolysis, and neurodegenerative diseases

Tang

2020

Journal Cellular Physiology

121

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Prolonged survival of a typical postmitotic neuron hinges on a balance between multiple processes, among these are a sustenance of ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both a drop in ATP levels, as well as increase reactive oxygen species production from inefficient electron transport processes and NADPH‐oxidases activities. The former often resulted in the phenomenon of compensatory aerobic glycolysis. The latter stretches the capacity of the cell's redox buffering capacity, and may lead to damages of key enzymes involved in energy metabolism. Several recent reports have indicated that enhancing glucose availability and uptake, as well as increasing glycolytic flux via pharmacological or genetic manipulation of glycolytic enzymes, could be protective in animal models of several major neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Activation of canonical Wnt signaling, which improves disease symptoms in mouse models of Alzheimer's disease also appears to work via an elevation of glycolytic enzymes and enhance glucose metabolism. Here, I discuss these findings and the possible underlying mechanisms of how an increase in glucose uptake and glycolysis could be neuroprotective. Increased glycolytic production of ATP would help alleviate energy deficiency, and ATP's hydrotropic effect may enhance solubility and clearance of toxic aggregates prevalent in many neurodegenerative diseases. Furthermore, channeling of glucose into the Pentose Phosphate Pathway would increase the redox buffering capacity of the cell.

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Reduction of Glycolysis Intermediate Concentrations in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

Cited by 30 publications

References 20 publications

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma

Glucose, glycolysis, and neurodegenerative diseases

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