ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.

Autor: Kawatani K; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Holm ML; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Starling SC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Martens YA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; SciNeuro Pharmaceuticals, Rockville, MD, 20850, USA., Zhao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, 32224, USA., Lu W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, 32224, USA., Ren Y; Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, 32224, USA., Li Z; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Jiang P; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Jiang Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Baker SK; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Wang N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Roy B; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA., Parsons TM; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, 32224, USA., Perkerson RB 3rd; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, 32224, USA., Bao H; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA., Han X; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China., Kanekiyo T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. kanekiyo.takahisa@mayo.edu.; Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, 32224, USA. kanekiyo.takahisa@mayo.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Mar; Vol. 29 (3), pp. 809-819. Date of Electronic Publication: 2023 Dec 22.
DOI: 10.1038/s41380-023-02372-w
Abstrakt: ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency-induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids. Furthermore, ABCA7-deficient iPSC-derived neurons showed compromised mitochondrial respiration and excess ROS generation, as well as enlarged mitochondrial morphology compared to the isogenic controls. ABCA7 deficiency also decreased spontaneous synaptic firing and network formation in iPSC-derived neurons, in which the effects were rescued by supplementation with phosphatidylglycerol or NAD + precursor, nicotinamide mononucleotide. Importantly, effects of ABCA7 deficiency on mitochondria morphology and synapses were recapitulated in synaptosomes isolated from the brain of neuron-specific Abca7 knockout mice. Together, our results provide evidence that ABCA7 loss-of-function contributes to AD risk by modulating mitochondria lipid metabolism.
(© 2023. The Author(s).)
Databáze: MEDLINE
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