Sex-specific lipid dysregulation in the Abca7 knockout mouse brain

YuHong Fu; Ying He; Katherine Phan; Russell Pickford; Young-Bum Kim; Nicolas Dzamko; Glenda M Halliday; Woojin Scott Kim

doi:10.1093/braincomms/fcac120

Sex-specific lipid dysregulation in the Abca7 knockout mouse brain

Brain Commun. 2022 May 11;4(3):fcac120. doi: 10.1093/braincomms/fcac120. eCollection 2022.

Authors

YuHong Fu^{1

2}, Ying He^{1

2}, Katherine Phan^{1

2}, Russell Pickford³, Young-Bum Kim⁴, Nicolas Dzamko^{1

2}, Glenda M Halliday^{1

2

5}, Woojin Scott Kim^{1

2

5}

Affiliations

¹ Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
² Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.
³ Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia.
⁴ Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁵ School of Medical Sciences, University of New South Wales & Neuroscience Research Australia, Sydney, NSW, Australia.

Abstract

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-β 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-β 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-β levels in the Abca7 knockout mice and found elevated free cholesterol only in female mice that was significantly correlated with amyloid-β42 levels. In male Abca7 knockout mice, the neuroprotective ganglioside GD1a levels were elevated and inversely correlated with amyloid-β42 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.

Keywords: ABCA7; Alzheimer’s disease; cholesterol; lipid dysregulation; lipidomics.