ABCA7 Regulates Brain Fatty Acid Metabolism During LPS-Induced Acute Inflammation

Abstract

The ATP binding cassette subfamily A member 7 (ABCA7) gene is one of the significant susceptibility loci for Alzheimer's disease (AD). Furthermore, ABCA7 loss of function variants resulting from premature termination codon in the gene are associated with increased risk for AD. ABCA7 belongs to the ABC transporter family, which mediates the transport of diverse metabolites across the cell membrane. ABCA7 is also involved in modulating immune responses. Because the immune system and lipid metabolism causatively engage in the pathogenesis of AD, we investigated how ABCA7 haplodeficiency modulates the metabolic profile in mouse brains during acute immune response using a metabolomics approach through LC/Q-TOF-MS. Peripheral lipopolysaccharide (LPS) stimulation substantially influenced the metabolite content in the cortex, however, the effect on metabolic profiles in Abca7 heterozygous knockout mice (Abca7 ^±) was modest compared to that in the control wild-type mice. Weighted gene co-expression network analysis (WGCNA) of the metabolomics dataset identified two modules influenced by LPS administration and ABCA7 haplodeficiency, in which glycerophospholipid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism were identified as major pathways. Consistent with these findings, we also found that LPS stimulation increased the brain levels of eicosapentaenoic acid, oleic acid, and palmitic acid in Abca7 ^± mice, but not control mice. Together, our results indicate that ABCA7 is involved in the crosstalk between fatty acid metabolism and inflammation in the brain, and disturbances in these pathways may contribute to the risk for AD.

Keywords: ABCA7; Alzheimer’s disease; fatty acids; inflammation; lipopolysaccharide; metabolomics.

FIGURE 1

Influence of ABCA7 haplodeficiency on LPS-induced metabolomic changes in mouse brains. Metabolomics was conducted in the cortex of control and Abca7^± mice (N = 6/each) administrated with or without LPS. (A) Principal component analysis (PCA) of metabolites from control and Abca7^± mice with or without LPS administration. (B) Venn diagram of the metabolites differently induced by LPS administration in control and/or Abca7^± mice.

FIGURE 2

Impact of ABCA7 haplodeficiency and peripheral LPS stimulation on mouse cortical metabolomes. (A) The correlation between metabolite module eigengenes and the four groups of mice: (1) control with LPS administration, (2) Abca7^± with LPS administration, (3) control with LPS administration, and (4) Abca7^± with LPS administration. Each module is represented with a unique color. The module traits were correlated with the four groups of mice (1–4). The corresponding correlations and P-values are displayed in each module. (B,C) The interactions of top 30 hub metabolites within the lightgreen (B) and paleturquoise (C) modules were visualized. (D) Pathway analysis of metabolites using the KEGG database. Pathways in the lightgreen (B) and paleturquoise (C) modules are shown (raw p-value < 0.05).

FIGURE 3

Altered effects of LPS stimulation on brain non-esterified fatty acid levels in heterozygous ABCA7 knockout mice. The amounts of non-esterified fatty acids (NEFAs) were analyzed through mass spectrometry in the cortex of control (A; white) and Abca7^± (B; gray) mice administrated with or without LPS. Concentration of myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, arachidonic acid, α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were plotted. All NEFA concentrations were normalized to the protein levels. Horizontal lines, boxes, and whiskers correspond to median, interquartile range (IQR), and the furthest points within 1.5 × IQR from the box, respectively (N = 6/each). *p < 0.05, **p < 0.01, by student-t test.