ABCA7 links sterol metabolism to the host defense system: Molecular background for potential management measure of Alzheimer's disease

Abstract

ATP-binding cassette transporter (ABC) A7 is a membrane protein that belongs to the large family of ABC transporters. It is 54% homologous in amino acid residue sequence to ABCA1 which mediates biogenesis of plasma high density lipoprotein (HDL) from cellular phospholipid and cholesterol with extracellular helical apolipoproteins such as apolipoprotein (apo) A-I. When transfected and expressed, ABCA7 also mediates generation of HDL-like particles but small and of less cholesterol content. However, endogenous ABCA7 is unlikely involved in HDL biogenesis and rather to regulate the host-defense system such as phagocytotic function of the cells. ABCA1 expression is regulated by cellular cholesterol levels, positively by the liver X receptor (LXR) in extrahepatic peripheral cells. However, it is modulated dually in the liver being relevant to transport of cholesterol for its catabolism; positively by LXR and negatively by sterol regulatory element binding protein (SREBP) or hepatic nuclear factor 4α (HNF4α). In contrast, ABCA7 expression was shown to be regulated negatively by the SREBP system so that decrease of cell cholesterol enhances ABCA7 function such as cellular phagocytotic reaction, suggesting that it links cholesterol metabolism to the host defense system. The interest is being build up in ABCA7 as its genomic diversity has been found related to a risk for late-onset Alzheimer's diseases. More recent findings indicate that ABCA7 is involved in metabolism of amyloid β peptide including its phagocytotic clearance. Accordingly, modulation of ABCA7 activity by manipulating cholesterol metabolism may open a new path for management of Alzheimer's disease.

Keywords: ABC transporter; Alzheimer’s disease; Cholesterol; High density lipoprotein; Phagocytosis.

Fig. 1.

Generation of HDL-like particles by ABCA1 and ABCA7 which are transfected in HEK293 cells in ecdysone-inducible forms (Hayashi et al., 2005). Their expression were linearly proportional to concentration of ponasterone, an ecdysone analogue, (A), and apoA-I mediated cell lipid release was exponentially increased by ABCA1 whereas linearly by ABCA7 (B). HPLC analysis of the HDL-like products showed two peaks for ABCA1-generated particles and a single peak for ABCA7-generated particles (C).

Fig. 2.

Putative structures of the promoters of ABCA1 (Costet et al., 2000) and ABCA7 (Iwamoto et al., 2006).

Fig. 3.

Negative regulation of ABCA7 expression and its function by cell cholesterol via SREBP. Expression of ABCA1 and ABCA7 are regulated in opposite directions by cell cholesterol in BALB/3T3 cells (A) and the responsible site for this regulation is SRE coded between positions −296 to −196 (SRE-1) (B) (Iwamoto et al., 2006). Accordingly, phagocytosis was upregulated by various statins in J774 cells (C) (Tanakaet al., 2011a).

Fig. 4.

Accumulation amyloid β peptides in the mouse brain by deficiency of ABCA7. Increase in soluble amyloid β in the brain of the APP-transgenic mice by deficiency of ABCA7 (A) (Satoh et al., 2015). ABCA7-dependent phagocytosis is responsible for amyloid β clearance by microglia in mouse brain (B) (Fu et al., 2016).