Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer’s disease astrocytes

Data availability: The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. Additional data and information is available on request from the authors.Supplementary information is available online at: https://www.nature.com/articles/s41380-024-02746-8#Sec34.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.This research was funded by Wellcome 4ward North (Ref: 216340/Z/19/Z), ARUK Yorkshire Network Centre Small Grant Scheme, ARUK Preparatory Clinical Fellowship scheme (Ref: ARUK-PCRF2016A-1), Academy of Medical Sciences Starter Grants for Clinical Lecturers Scheme (Ref: SGL028\1097), Parkinson’s UK (Ref: F1301), Michael J Fox Foundation (Ref: 005021), Australian Research Council (CE200100012), European Union Seventh Framework Programme (Ref: FP7/2007–2013) under grant agreement no. 601055, and the NIHR Sheffield Biomedical Research Centre award (NIHR 203321)

Neurokinin B and pre-eclampsia: a decade of discovery

ABSTRACT: At the start of the last decade, we provided evidence that levels of the peptide neurokinin B were highly elevated in pre-eclampsia. We hypothesized that elevated levels of neurokinin B may be an indicator of pre-eclampsia and that treatment with certain neurokinin receptor antagonists may be useful in alleviating the symptoms. At the time of the original hypothesis many questions remained outstanding. These included - Does neurokinin B have any diagnostic value in the detection and diagnosis of pre-eclampsia? - What is the cause of the elevated levels of neurokinin B during pre-eclampsia? - What is the physiological significance of neurokinin B in the placenta? This review discusses the answers to these questions taking into account the subsequent developments of the past ten years and analyzing the plethora of discoveries that have arisen from those initial observations