Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias

Bonomi, Chiara Giuseppina; Lucia, Vincenzo De; Mascolo, Alfredo Paolo; Assogna, Martina; Motta, Caterina; Scaricamazza, Eugenia; Sallustio, Fabrizio; Mercuri, Nicola Biagio; Koch, Giacomo; Martorana, Alessandro

doi:10.1016/j.neurobiolaging.2021.05.011

Cited by 16 publications

(12 citation statements)

References 53 publications

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“…As the common metabolites of glycolysis and pentose phosphate pathway, the levels of glucose 6-phosphate, fructose 6-phosphate, fructose 1,6-bisphosphate, glyceraldehyde 3-phosphate, and pyruvate were increased in the d -gal group; however, the lactate level was decreased. Lactate is the downstream reduction product of pyruvate in the brain, which is usually released from the process of astrocytes consuming glucose to generate pyruvate and activating lactolysis for energy supply by neurons. , A low lactate level in the CSF of AD patients has been confirmed, which goes along with neurodegeneration . The increased lactate level in the d -gal + GAA group implied that the energy supply of neurons had been restored by means of lactolysis.…”

Section: Discussionmentioning

confidence: 94%

“…39,45 A low lactate level in the CSF of AD patients has been confirmed, which goes along with neurodegeneration. 46 The increased lactate level in the D-gal + GAA group implied that the energy supply of neurons had been restored by means of lactolysis. The pentose phosphate pathway provided NAPDH to fatty acid βoxidation, which then produced acetyl-CoA into the TCA cycle as the energy supply.…”

Section: ■ Discussionmentioning

confidence: 98%

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Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

Wang

Yang

et al. 2021

J. Agric. Food Chem.

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Ganoderic acid A (GAA) is a kind of lanostane-type triterpenoid isolated from Ganoderma lucidum. Imbalance of the Th17/Tregs axis exists in the progress of neuroinflammation of Alzheimer's disease (AD). In this study, the alleviating neuroinflammatory effect of GAA on D-galactose mice was studied from the aspect of regulating the imbalance of the Th17/Tregs axis. The Morris water maze test was used to evaluate the cognitive ability of AD mice. Flow cytometry was used to detect the percentages of IL-17A, IL-17F, IL-21, IL-22, and CD4 + CD25 + Foxp3 + in peripheral blood. Transmission electron microscopy was used to assess the cerebral mitochondrial ultrastructure. Metabolomic analysis based on gas chromatography−mass spectrometry was used to evaluate the mitochondrial dysfunction metabolism. Western blot analysis was used to detect the protein expressions of cytokines secreted by Th17 cells and Treg cells in the brain. As the results show, GAA has an alleviating neuroinflammatory effect on AD mice via regulating the imbalance of the Th17/Tregs axis. The potential mechanism was related to inhibition of the JAK/STAT signaling pathway induced by Th17 cells and enhancement of the mitochondrial oxidative phosphorylation by regulating Treg cells, thereby improving mitochondrial dysfunction of AD mice.

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Section: Discussionmentioning

confidence: 94%

Section: ■ Discussionmentioning

confidence: 98%

Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

Wang

Yang

et al. 2021

J. Agric. Food Chem.

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“…Of relevance, mitochondrial dysfunction, which is associated with age-related neurodegeneration, is also particularly important in AD (Beal, 2005;Yao and Brinton, 2011). In line with the decreased glycolysis in AD brains, an interesting recent study showed that levels of lactate were reduced in the CSF of patients with AD, although no correlation were found between CSF lactate and amyloid levels (Bonomi et al, 2021). Recently, physical exercise was found to have beneficial effects in AD through the improvement of brain glucose metabolism.…”

Section: Brain Energy Metabolic Dysfunctions In Aging and Neurodegenerative Diseasesmentioning

confidence: 99%

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

et al. 2022

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Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

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“…Higher CSF glucose levels have been found to be associated with less tau pathology in the brain 48 . A reduction in CSF lactate has been observed in AD which was suggested to be linked to tauopathy 49 . In our data, we observe that increased abundance of glycolytic enzymes is correlated with lower CSF glucose, potentially indicating an increased cellular uptake of glucose through upregulated glucose transporters.…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer’s disease in a large clinical sample

de Geus,

Leslie,

Lam

et al. 2023

Sci Rep

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Alzheimer’s disease (AD) is a complex and heterogeneous neurodegenerative disorder with contributions from multiple pathophysiological pathways. One of the long-recognized and important features of AD is disrupted cerebral glucose metabolism, but the underlying molecular basis remains unclear. In this study, unbiased mass spectrometry was used to survey CSF from a large clinical cohort, comparing patients who are either cognitively unimpaired (CU; n = 68), suffering from mild-cognitive impairment or dementia from AD (MCI-AD, n = 95; DEM-AD, n = 72), or other causes (MCI-other, n = 77; DEM-other, n = 23), or Normal Pressure Hydrocephalus (NPH, n = 57). The results revealed changes related to altered glucose metabolism. In particular, two glycolytic enzymes, pyruvate kinase (PKM) and aldolase A (ALDOA), were found to be upregulated in CSF from patients with AD compared to those with other neurological conditions. Increases in full-length PKM and ALDOA levels in CSF were confirmed with immunoblotting. Levels of these enzymes furthermore correlated negatively with CSF glucose in matching CSF samples. PKM levels were also found to be increased in AD in publicly available brain-tissue data. These results indicate that ALDOA and PKM may act as technically-robust potential biomarkers of glucose metabolism dysregulation in AD.

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Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias

Cited by 16 publications

References 53 publications

Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer’s disease in a large clinical sample

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