*3.2. Role of ABCA7 in Phagocytosis and Immune Response*

In their initial investigation about ABCA7 sequence genomic organization, Kaminski et al. also observed that ABCA7 is arranged in a head-to-tail array with the human minor histocompatibility antigen HA-1 in a common locus on the 19p13.3 chromosome [11]. Since HA-1 is implicated in host defense, and based on its physical proximity to ABCA7, the question about possible common regulatory and functional mechanisms between these two genes was quickly raised [11]. Another clue suggesting a role of ABCA7 in immunity is the high sequence homology of the ABCA7 gene with cell death proteins (*Ced*) genes. In *Caenorhabditis elegans*, *ced* genes are key players of engulfment of dying cells. Among all these proteins, CED-7 is required for CED-1 functioning. Interestingly, mammalian orthologues have been proposed for all *Ced* genes, based on their sequence homologies. ABCA1 and ABCA7 have been proposed as being orthologues for CED7 [41], and low-density lipoprotein receptor–related protein 1 (LRP1) has been suggested as a protein with similar function to CED-1 [42]. In macrophages, ABCA7 and LRP1 were relocalized together to the plasma membrane in the presence of apoptotic cells, thus promoting their engulfment. Macrophages blocked with an antibody against LRP1 or *Abca7*+/- macrophages show both lower phagocytosis of these dying cells, as well as a decrease of the ERK phosphorylation, highlighting links between this ABC transporter, LRP1 and this signaling pathway [41]. ABCA7 expression and mediated phagocytosis are also increased when cholesterol synthesis is inhibited by statins that block HMG-CoA activity [38], demonstrating again strong relationships between cellular cholesterol pool and ABCA7 activity and expression.

As indicated above, ABCA7 is also able to interact with ApoA-I and HDL. Therefore, a potential contribution of (apo)lipoproteins in phagocytosis was investigated by Tanaka et al. They reported that extracellular HDL increases ABCA7-associated phagocytosis by stabilizing ABCA7, thus suggesting an involvement of the HDL components in the host defense system that deserves further investigation [38].

Therefore, a possible role of ABCA7 in host defense was clearly established and investigated by several studies reporting the ABCA7 implication in phagocytosis-mediated processes by macrophages instead of cholesterol regulation.

However, until 2011, no study clearly demonstrated a key role of ABCA7 in a human disease. When Hollingworth et al. published that single nucleotide polymorphisms (SNPs) in ABCA7 sequences were strongly associated with Alzheimer's disease (AD) onset and development [12], a new field of investigation has emerged with the objectives to identify the exact function of ABCA7 in the brain as well as in the apparition and evolution of AD.
