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Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.
Bell, Simon M; Wareing, Hollie; Capriglia, Francesco; Hughes, Rachel; Barnes, Katy; Hamshaw, Alexander; Adair, Liam; Shaw, Allan; Olejnik, Alicja; De, Suman; New, Elizabeth; Shaw, Pamela J; De Marco, Matteo; Venneri, Annalena; Blackburn, Daniel J; Ferraiuolo, Laura; Mortiboys, Heather.
Afiliación
  • Bell SM; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK. s.m.bell@sheffield.ac.uk.
  • Wareing H; NIHR Sheffield Biomedical Research Centre, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. s.m.bell@sheffield.ac.uk.
  • Capriglia F; Neuroscience Institute, University of Sheffield, Firth Court, Sheffield, S10 2TN, UK. s.m.bell@sheffield.ac.uk.
  • Hughes R; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Barnes K; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Hamshaw A; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Adair L; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Shaw A; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Olejnik A; School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia.
  • De S; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, 2006, Australia.
  • New E; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Shaw PJ; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • De Marco M; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Venneri A; School of Chemistry, The University of Sydney, Sydney, NSW, 2006, Australia.
  • Blackburn DJ; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, 2006, Australia.
  • Ferraiuolo L; Sheffield Institute for Translational Neuroscience, School of Medicine and Population Health, University of Sheffield, 385a Glossop Rd, Sheffield, S10 2HQ, UK.
  • Mortiboys H; NIHR Sheffield Biomedical Research Centre, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
Mol Psychiatry ; 2024 Sep 13.
Article en En | MEDLINE | ID: mdl-39271753
ABSTRACT
Abnormalities in cellular metabolism are seen early in Alzheimer's disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients' astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido