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ABCA7 deficiency compromises astrocytic lipid homeostasis and impairs neuronal support

ABSTRACT: Loss-of-function variants in ABCA7 are well-established genetic risk factors for Alzheimer’s disease (AD), yet its role in glial cells remains unclear. Single-cell transcriptomic analysis of glia-enriched cortical organoids from isogenic control and ABCA7 knockout induced pluripotent stem cells (iPSCs) revealed cell type-specific effects of ABCA7 deficiency, including mitochondrial metabolism- and stress-associated signatures in astrocyte populations. Lipidomic profiling revealed extensive remodeling in ABCA7-deficient iPSC-derived astrocytes, characterized by reduced cholesteryl esters, cholesterol, sphingomyelin, phosphatidylcholine, lysophosphatidylethanolamine and phosphatidylserine, and increased cardiolipin. These lipid alterations were accompanied by impaired cholesterol efflux and reduced lipid droplet formation. While mitochondrial respiration and glycolysis were heightened in ABCA7-deficient iPSC-derived astrocytes compared to controls, we found the increased mitochondrial reactive oxygen species and exacerbated ferroptosis-related phenotype. ABCA7-deficient iPSC-derived astrocytes were functionally impaired in their ability to support neurite extension and neuronal activity, an effect partially rescued by treatment with the iron chelator deferoxamine mesylate. Our findings identified ABCA7 as a critical regulator of metabolic homeostasis in astrocytes, providing mechanistic insight into how ABCA7 dysfunction may contribute to AD pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE345792 | GEO | 2026/09/07

REPOSITORIES: GEO

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Project description:Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio circa 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 dynamics 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-beta 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.

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ABCA7 deficiency compromises astrocytic lipid homeostasis and impairs neuronal support

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