Sex-specific lipid dysregulation in the Abca7 knockout mouse brain

Fu et al. report sex-specific differences in brain lipids that are trafficked through the Abca7 transporter, suggesting a potential basis for the sex-specific differences in the aetiology of Alzheimer's disease. Alzheimer's disease is a devastating neurodegenerative disease that affects more women than men. The pathomechanism underlying the sex disparity, especially in the brain, is unclear. ABCA7 is one of the strongest susceptibility genes for Alzheimer's disease. It mediates the transport of lipids across membranes and is associated with pathways related to amyloid-beta neuropathology. However, the role of ABCA7 in the regulation of brain lipids is largely unknown. Sex-specific differences in the pathological link between brain lipid dysregulation and amyloid-beta are also unknown. Here, we undertook quantitative discovery lipidomics of male and female Abca7 knockout (n = 52) and wild type (n = 35) mouse brain using sophisticated liquid chromatography/mass spectrometry. We identified 61 lipid subclasses in the mouse brain and found sex-specific differences in lipids that were altered with Abca7 deletion. The altered lipids belong to cellular pathways that control cell signalling, sterol metabolism, mitochondrial function and neuroprotection. We also investigated the relationship between lipids and amyloid-beta levels in the Abca7 knockout mice and found elevated free cholesterol only in female mice that was significantly correlated with amyloid-beta 42 levels. In male Abca7 knockout mice, the neuroprotective ganglioside GD1a levels were elevated and inversely correlated with amyloid-beta 42 levels. Collectively, these results demonstrate that Abca7 deletion leads to sex-specific lipid dysregulation in the brain, providing insight into the underlying sex disparity in the aetiology of Alzheimer's disease.