ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism

Keiji Kawatani, Marie Louise Holm, Skylar C. Starling, Yuka A. Martens, Jing Zhao, Wenyan Lu, Yingxue Ren, Zonghua Li, Peizhou Jiang, Yangying Jiang, Samantha K. Baker, Ni Wang, Bhaskar Roy, Tammee M. Parsons, Ralph B. Perkerson, Hanmei Bao, Xianlin Han, Guojun Bu, Takahisa Kanekiyo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)809-819
Number of pages11
JournalMolecular psychiatry
Volume29
Issue number3
DOIs
StatePublished - Mar 2024

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology

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