Amyloid β 1-42 Induces Hypometabolism in Human Stem Cell-Derived Neuron and Astrocyte Networks
Open accessAbstract
Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (A β1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD + /NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from A β-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with A β-induced hypometabolism.
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Aβ induces a decrease in glucose uptake by reducing the availability of GLUT1, which amplifies the decrease in glycolysis.
“In turn, A β , in a vicious circle, induces a decrease in glucose uptake, notably by reducing the availability of GLUT1, the plasma membrane transporter of glucose, which amplifies the decrease in glycolysis (Hendrix et al., 2021; Tarczyluk et al., 2015)”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Tarczyluk et al., 2015
The Results section (‘Glucose Uptake Is Decreased After Treatment with Amyloid Beta’; page unavailable) reports reduced glucose uptake after Aβ treatment. The Discussion suggests inhibition of glycolysis, but proposes that this leads to glucose accumulation and reduced uptake—not that reduced uptake amplifies glycolytic inhibition. Our copy does not identify reduced GLUT1 availability as the mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn vitro addition of Aβ reduces astrocytic glucose uptake.
“In vitro addition of A β in the culture medium reduces astrocytic glucose uptake (Tarczyluk et al., 2015)”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Tarczyluk et al., 2015
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Ceyzériat, K., Badina, A. M., Petrelli, F., Montessuit, S., Nicolaides, A., Millet, P., Savioz, A., Martinou, J.-C., & Tournier, B. B. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106623 · Cited by 18 · see citing works
- Authors
- Tarczyluk, M. A., Nagel, D. A., Parri, H. R., Tse, E. H., Brown, J. E., Coleman, M. D., & Hill, E. J.
- Affiliations
- Department of Basic and Clinical Neuroscience, James Black Centre, Institute of Psychiatry, London, UK
- Aston University (GB)
- Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham, UK.
- Corresponding author
- Hill, Eric J
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2015-04-08
- Volume
- 35
- Issue
- 8
- Pages
- 1348-1357
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC4528011
- OpenAlex
- W1972047429
- Cited by
- 42
- References
- 2
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 1 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 8 · 2015: 1
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Aston Publications Explorer (Aston University) (acceptedVersion)
- Aston Publications Explorer (Aston University) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta 42, oligomers, brain hypometabolism, Alzheimer's disease, astrocytes, energy metabolism, glucose utilization, lactate, glutamate, glycogen, NAD+/NADH ratio, ATP, glutathione, oxidative stress
- MeSH terms
- Alzheimer Disease, Astrocytes, Energy Metabolism, Humans, Models, Biological, Nerve Net, Neurons, Peptide Fragments, Stem Cells, Amyloid beta-Peptides, Oxidative Stress, Cell Line, Tumor
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