The role of APOE and ABCA7 in lipid metabolism for late-onset Alzheimer's disease
File(s)
Author(s)
Zhong, Qi
Type
Thesis
Abstract
According to genome-wide association studies, a large number of Alzheimer’s disease (AD)-related variants are involved in lipid metabolism, implying the correlation of lipid dysregulation and AD pathogenesis. Variants in genes that encode lipid transporters, including the APOEε4 allele and loss-of-function single nucleotide polymorphisms in ABCA7, are strongly associated with an increased risk of AD, especially late-onset AD. Although lipidomics has begun to uncover lipid pathways affected by these genetic variants, systemic and brain cell-specific lipid alterations caused by their expression remain unknown. The aim of this study was to determine the effects of APOE4 and loss-of-function mutation of ABCA7 on lipid metabolism at the tissue and cellular levels. In this study, I conducted untargeted lipidomic profiling using ultrahigh-performance liquid chromatography coupled with ion-mobility quadrupole time-offlight
mass spectrometry. Analyses were performed on brain, plasma, and peripheral tissues from humanised APOE knock-in mice overexpressing human islet amyloid polypeptide (hIAPP) and homozygous ABCA7 knock-out mice. To investigate lipid changes at the cellular level, I also profiled iPSC-derived microglia expressing different APOE genotypes, and ABCA7-/- iPSC-derived microglia. In the brains of both 6-month-old APOE4/4 hIAPP and ABCA7-/-
mice, a downregulation of polyunsaturated fatty acid-containing glycerophospholipids, including plasmalogens, was observed. These glycerophospholipids include docosahexaenoic acid and arachidonic acid (ARA), which are essential for cognitive function. While peripheral apoE
is usually separated from apoE in the brain, I also detected elevated levels of ARA-derived pro-inflammatory eicosanoids in the liver of 6-month APOE4/4 mice, which implied peripheral APOE4 expression may also contribute to AD pathogenesis. At the cellular level, changes in sphingolipid metabolism, particularly involving ceramides, were consistently observed in both APOE4/4 and ABCA7-/- iPSC-derived microglia compared to controls. Understanding the shared alterations in lipid pathways caused by these AD risk factors can reveal the targetable mechanisms for disease progression and provide new avenues of treatment.
mass spectrometry. Analyses were performed on brain, plasma, and peripheral tissues from humanised APOE knock-in mice overexpressing human islet amyloid polypeptide (hIAPP) and homozygous ABCA7 knock-out mice. To investigate lipid changes at the cellular level, I also profiled iPSC-derived microglia expressing different APOE genotypes, and ABCA7-/- iPSC-derived microglia. In the brains of both 6-month-old APOE4/4 hIAPP and ABCA7-/-
mice, a downregulation of polyunsaturated fatty acid-containing glycerophospholipids, including plasmalogens, was observed. These glycerophospholipids include docosahexaenoic acid and arachidonic acid (ARA), which are essential for cognitive function. While peripheral apoE
is usually separated from apoE in the brain, I also detected elevated levels of ARA-derived pro-inflammatory eicosanoids in the liver of 6-month APOE4/4 mice, which implied peripheral APOE4 expression may also contribute to AD pathogenesis. At the cellular level, changes in sphingolipid metabolism, particularly involving ceramides, were consistently observed in both APOE4/4 and ABCA7-/- iPSC-derived microglia compared to controls. Understanding the shared alterations in lipid pathways caused by these AD risk factors can reveal the targetable mechanisms for disease progression and provide new avenues of treatment.
Date Issued
2025-05-09
Date Awarded
2026-02-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Griffin, Julian
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)