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

• Published in: Gene Vol. 768; p. 145316
• Main Authors: Abe-Dohmae, Sumiko, Yokoyama, Shinji
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.02.2021
• Subjects: ABC transporter; Alzheimer Disease - metabolism; Alzheimer’s disease; Animals; ATP-Binding Cassette Transporters - metabolism; Cholesterol; Cholesterol - metabolism; Hepatocyte Nuclear Factor 4; High density lipoprotein; Humans; Liver X Receptors - metabolism; Phagocytosis; Sterol Regulatory Element Binding Proteins; Sterols - metabolism; apo; HNF; ABC; SREBP; HMG; Alzheimer’s disease; SRE; LXR; High density lipoprotein; TMD; Cholesterol; NBD; HDL; LDL; ABC transporter; Phagocytosis
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2020.145316

•ABCA7 is highly homologous to ABCA1 and mediates HLD generation when transfected.•ABCA7 unlikely plays a significant role in HDL metabolism in vivo.•ABCA7 is down regulated by cell cholesterol and associated with phagocytosis.•Genome-wide association studies identified ABCA7 as a risk gene of late-onset Alzheimer’s disease.•ABCA7 deficiency causes less phagocytosis activity and amyloid-β accumulation. 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.