Deficits in mitochondrial function and glucose metabolism seen in sporadic and familial Alzheimer’s disease derived Astrocytes are ameliorated by increasing hexokinase 1 expression
Open accessAbstract
Background: Astrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitter synaptic homeostasis. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The neuronal support provided by astrocytes has a high metabolic demand. Deficits in astrocytic mitochondrial metabolic functioning and glycolysis could impair neuronal function. Changes to cellular metabolism are seen early in Alzheimer’s disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti-amyloid treatments in AD. Methods: In this project, we characterised mitochondrial and glycolytic function in astrocytes derived from patients with sporadic (n=6) and familial (PSEN1, n=3) forms of AD. Astrocytes were derived using direct reprogramming methods. Astrocyte metabolic outputs: ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene. Results: There was a reduction of total cellular ATP of 20% (p=0.05 in sAD astrocytes) and of 48% (p<0.01) in fAD. A 44% reduction (p<0.05), and 80% reduction in mitochondrial spare capacity was seen in sAD and fAD astrocytes respectively. Reactive oxygen species (ROS) were increased in both AD astrocyte types (p=0.05). Mitochondrial complex I and II was significantly increased in sAD (p<0.05) but not in fAD. Astrocyte glycolytic reserve and extracellular lactate was significantly reduced when compared to controls in both sAD and fAD (p<0.05). We identified a deficit in the glycolytic pathway enzyme hexokinase, and correcting this deficit restored most of the metabolic phenotype in sAD but not fAD astrocytes. Conclusion: AD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These functional deficits can be improved by correcting hexokinase expression deficits with adenoviral vectors. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Reduced astrocyte lactate production and astrocytic glycolysis (hexokinase activity) have been observed in both familial and sporadic forms of Alzheimer's disease.
“Indeed, reduced astrocyte lactate production and astrocytic glycolysis (i.e. hexokinase activity) have been observed in both familial and sporadic forms of the disease, making this inhibition a ubiquitous mechanism in AD (Bell et al., 2023; Le Douce et al., 2020; Zhang et al., 2022).”
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 Bell et al., 2023
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Mertens, J., Paquola, A. C. M., Ku, M., Hatch, E., Böhnke, L., Ladjevardi, S., McGrath, S., Campbell, B., Lee, H., Herdy, J. R., et al. (2015) · Cell Stem Cell · doi:10.1016/j.stem.2015.09.001 · Cited by 765 · see citing works
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · see citing works
PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease
Oksanen, M., Petersen, A. J., Naumenko, N., Puttonen, K., Lehtonen, Š., Gubert Olivé, M., Shakirzyanova, A., Leskelä, S., Sarajärvi, T., Viitanen, M., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.016 · Cited by 332 · see citing works
Garwood, C. J., Ratcliffe, L. E., Simpson, J. E., Heath, P. R., Ince, P. G., & Wharton, S. B. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12338 · Cited by 233 · see citing works
Reddy, P. H. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.06.012 · Cited by 147 · see citing works
Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients
Curti, D., Rognoni, F., Gasparini, L., Cattaneo, A., Paolillo, M., Racchi, M., Zani, L., Bianchetti, A., Trabucchi, M., Bergamaschi, S., et al. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00741-6 · Cited by 80 · see citing works
Flagged first, then by citations
Research works printed but not linked: 18
- Bekris, L.M., et al., Genetics of Alzheimer disease. Journal of geriatric psychiatry and neurology, 2010. 23(4): p. 213-227.
- van Dyck, C.H., et al., Lecanemab in Early Alzheimer's Disease. New England Journal of Medicine, 2022.
- Wang, X., et al., Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. The American journal of pathology, 2008. 173(2): p. 470-482.
- Rose, I.A. and J.V.B. Warms, Mitochondrial Hexokinase: RELEASE, REBINDING, AND LOCATION. Journal of Biological Chemistry, 1967. 242(7): p. 1635-1645.
- Malik, N. and M.S. Rao, A review of the methods for human iPSC derivation. Methods in molecular biology (Clifton, N.J.), 2013. 997: p. 23-33.
- Baxter, M., et al., Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. Journal of hepatology, 2015. 62(3): p. 581-589.
- Mertens, J., et al., Aging in a Dish: iPSC-Derived and Directly Induced Neurons for Studying Brain Aging and Age-Related Neurodegenerative Diseases. Annual review of genetics, 2018. 52: p. 271-293.
- Ferraiuolo, L., et al., Oligodendrocytes contribute to motor neuron death in ALS via SOD1- dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America, 2016. 113(42): p. E6496-E6505.
- Schwartzentruber, A., et al., Oxidative switch drives mitophagy defects in dopaminergic <em>parkin</em> mutant patient neurons. bioRxiv, 2020: p. 2020.05.29.115782.
- Gatto, N., et al., Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell, UNDER REVIEW.
- Ferraiuolo, L., et al., Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain : a journal of neurology, 2011. 134(Pt 9): p. 2627-2641.
- Bigl, M., et al., Activities of key glycolytic enzymes in the brains of patients with Alzheimer's disease. Journal of Neural Transmission, 1999. 106(5-6): p. 499-511.
- Hashimoto, M., et al., Analysis of microdissected neurons by 18O mass spectrometry reveals altered protein expression in Alzheimer's disease. Journal of Cellular and Molecular Medicine, 2012. 16(8): p. 1686-1700.
- Bigl, M., et al., Changes of activity and isozyme pattern of phosphofructokinase in the brains of patients with Alzheimer's disease. Journal of Neurochemistry, 1996. 67(3): p. 1164-1171.
- Sorbi, S., et al., ALTERED HEXOKINASE-ACTIVITY IN SKIN CULTURED FIBROBLASTS AND LEUKOCYTES FROM ALZHEIMERS-DISEASE PATIENTS. Neuroscience Letters, 1990. 117(1-2): p. 165-168.
- Sibson, N.R., et al., Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proceedings of the National Academy of Sciences, 1998. 95(1): p. 316-321.
- Brooks, G.A., Cell-cell and intracellular lactate shuttles. J Physiol, 2009. 587(Pt 23): p. 5591- 600. 100. Pellerin, L. and P.J. Magistretti, Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences, 1994. 91(22): p. 10625-10629. 101. Herrero-Mendez, A., et al., The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol, 2009. 11(6): p. 747-52. 102.
- Simpson, J.E., et al., Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology. Neuropathol Appl Neurobiol, 2016. 42(2): p. 167-79. 103. Nunomura, A., et al., The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons. J Neuropathol Exp Neurol, 2012. 71(3): p. 233-41. 104. Nunomura, A., et al., RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci, 1999. 19(6): p. 1959-64. 105. Ota, Y., A.T. Zanetti, and R.M. Hallock, The role of astrocytes in the regulation of synaptic plasticity and memory formation. Neural Plast, 2013. 2013: p. 185463. 106. Pangršič, T., et al., Exocytotic Release of ATP from Cultured Astrocytes*. Journal of Biological Chemistry, 2007. 282(39): p. 28749-28758. 107. Tan, Z., et al., Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons. Nature Communications, 2017. 8(1): p. 13772. 108. Guzman, S.J. and Z. Gerevich, P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction. Neural Plast, 2016. 2016: p. 1207393. 109. Konttinen, H., et al., PPARβ/δ-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes. Glia, 2019. 67(1): p. 146-159. 110. Liemburg-Apers, D.C., et al., Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Arch Toxicol, 2015. 89(8): p. 1209-26. 111. Bubber, P., et al., Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol, 2005. 57(5): p. 695-703. 112. Zhang, C., R.A. Rissman, and J. Feng, Characterization of ATP alternations in an Alzheimer's disease transgenic mouse model. Journal of Alzheimer's disease : JAD, 2015. 44(2): p. 375- 378.
Cited by
Sorted by citations
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
- Bell, S. M., Wareing, H., Hamshaw, A., De, S., New, E., Shaw, P. J., De Marco, M., Venneri, A., Blackburn, D. J., Ferraiuolo, L., & Mortiboys, H.
- Affiliations
- University of Sheffield (GB)
- The University of Sydney (AU)
- Brunel University of London (GB)
- Corresponding author
- Mortiboys, Heather
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-03-25
- OpenAlex
- W4360938388
- Cited by
- 1
- References
- 6
- Citations by year
- 2024: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- Funders
- Wellcome Trust (216340/Z/19/Z)
- National Institute for Health and Care Research (FP7/2007–2013)
- Department of Health and Social Care
- Parkinson's UK (F1301)
- European Commission (601055, 2007–2013, FP7 2007-2013, FP7/2007)
- Sheffield Teaching Hospitals NHS Foundation Trust
- NIHR Sheffield Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, astrocytes, hexokinase 1, mitochondrial dysfunction, glycolysis, sporadic Alzheimer's disease, familial Alzheimer's disease, presenilin 1, reactive oxygen species, lactate, ATP production, adenoviral gene transfer, therapeutic target, astrocyte reprogramming, glycogen
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
