Journal Article Preprint Epublish 10 citations
PubMed: 38979214 DOI: 10.1101/2023.09.05.556135
ABCA7 Loss-of-Function Variants Impact Phosphatidylcholine Metabolism in the Human Brain.
bioRxiv
Authors: Djuna von Maydell, Shannon Wright, Ping-Chieh Pao, Colin Staab, Oisín King, Andrea Spitaleri, Julia Maeve Bonner, Liwang Liu, Chung Jong Yu, Ching-Chi Chiu, Daniel Leible, Aine Ni Scannail, Mingpei Li, Carles A Boix, Hansruedi Mathys, Guillaume Leclerc, Gloria Suella Menchaca, Gwyneth Welch, Agnese Graziosi, Noelle Leary, George Samaan, Manolis Kellis, Li-Huei Tsai
Affiliations
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
- Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
- Department of Medical Biotechnologies and Translational Medicine, University of Milano, Via F.lli Cervi 93, Segrate (MI), 20054 Italy.
- MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 02139, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
Abstract
Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio ≈ 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) - predicted by molecular dynamic simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-β secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimer's disease.
MeSH
Choline, Cells, Neurons, Respiration, Phosphatidylcholines, Triglycerides