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Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U, Kong A, Helisalmi S, Soininen H, Lah JJ, DemGene, Aarsland D, Fladby T, Ulstein ID, Djurovic S, Sando SB, White LR, Knudsen GP, Westlye LT, Selbæk G, Giegling I, Hampel H, Hiltunen M, Levey AI, Andreassen OA, Rujescu D, Jonsson PV, Bjornsson S, Snaedal J, Stefansson K. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat Genet. 2015 May;47(5):445-7. Epub 2015 Mar 25 PubMed.
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NHMRC Research Fellow
Loss-of-function variants in ABCA7 highlight an important role in Alzheimer’s disease
Early in vitro studies suggested that ABCA7 may play a protective role in Alzheimer’s disease (AD) (Chan et al., 2008). Interest in the association of ABCA7 with AD has grown rapidly due to the identification of ABCA7 SNPs that confer increased risk for AD (for example, see Hollingworth et al., 2011; Reitz et al., 2013; Shulman et al., 2013; Lambert et al., 2013; Carrasquillo et al., 2015; Yu et al., 2015). This new publication from Steinberg et al. provides further compelling evidence that ABCA7 is a clinically relevant contributor to AD risk. The authors identified ABCA7 loss-of-function variants in an Icelandic population that conferred increased AD risk (OR = 2.12). Although these variants may be rare, the study provides important new information highlighting the functional importance of ABCA7 in the brain. The overall conclusions suggest that reduced levels of the ABCA7 protein underlie the increase in AD risk associated with ABCA7 variants. Given the highly reproducible findings from several studies that confirm an association between ABCA7 and AD, it is now important to focus on the true biological function of ABCA7 in the brain. In a study of the association between the top 10 GWAS “hits” for AD risk and plaque pathology, ABCA7 was one of four genes found to be significantly associated with plaque burden (Shulman et al., 2013). Although numerous pathological processes may be influenced by ABCA7 in the brain, an assessment of its role in the regulation of plaque pathology appears to be the most logical place to start.
A recent study of ours provided evidence that loss of ABCA7 function has a profound impact on amyloid plaque pathology (Kim et al., 2013). We generated amyloidogenic J20 AD mice that were Abca7-deficient (J20/A7-/-) and discovered that their hippocampal amyloid plaque levels doubled compared to J20 littermates (Kim et al., 2013). We also showed that the clearance of oligomeric amyloid-β (Aβ) was impaired in phagocytic cells derived from Abca7-deficient mice as compared to wild-type-mouse-derived phagocytes (Kim et al., 2013). The questions that now need to be addressed are related to the identification of the precise mechanisms by which the ABCA7 protein regulates AD risk, and whether therapeutic manipulation of the pathways involved can be exploited to treat patients.
Although ABCA7 is a member of the “A” subfamily of ATP-binding cassette transporters that were initially characterized by their capacity to transport lipids across membranes (Kim et al., 2013), unlike its closest homologue (ABCA1), ABCA7 does not appear to play a major role in transporting cholesterol across cell membranes to lipid-free ApoE (Chan et al., 2008). Indeed, in the absence of Abca7 (in our J20/A7-/- mouse experiments), we found no evidence for a reduction in brain ApoE levels that would imply inadequate ApoE lipidation (Kim et al., 2013). ABCA7 functions that are not related to lipid transport should therefore be considered in the context of AD.
In addition to its similarity with ABCA1, ABCA7 shares sequence homology (24 percent identity, 43 percent similarity) with the C. elegans CED-7 protein (Jehle et al., 2006). CED-7 plays a crucial role in phagocytosis and it is recognized that ABCA7 also regulates phagocytosis in several mammalian cell types (Jehle et al., 2006; Iwamoto et al., 2006). These findings are in accord with the high expression of ABCA7 in macrophages and microglia (Kaminski et al., 2000; Kim et al., 2006). As ABCA7 is highly expressed in the brain (Kim et al., 2013; Kim et al., 2008), and this is particularly due to microglial expression (Kim et al., 2006), a function for ABCA7 in the phagocytic clearance of Aβ could explain the highly reproducible association of ABCA7 variants with increased AD risk. If a phagocytic role for ABCA7 is conclusively demonstrated (for example, in studies utilising myeloid cell conditional Abca7-deficient AD mice), a new AD therapeutic target could arise by virtue of a direct stimulation of oligomeric Aβ clearance by microglia. Such a pathway would also have implications for current Aβ immunotherapeutic strategies that ultimately depend on microglial phagocytic clearance of Aβ-antibody complexes. In showing that loss-of-function variations in ABCA7 confer AD risk, the new findings from Steinberg et al. place questions regarding the true function of ABCA7 protein in the brain at center stage.
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Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK, Cheng D, Karl T, Garner B. Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer's disease. J Neurosci. 2013 Mar 6;33(10):4387-94. PubMed.
Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem. 2008 Mar;104(5):1145-66. PubMed.
Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, Vandivier RW, Wang N, Greenberg S, Dale BM, Qin C, Henson PM, Tall AR. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol. 2006 Aug 14;174(4):547-56. PubMed.
Iwamoto N, Abe-Dohmae S, Sato R, Yokoyama S. ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis. J Lipid Res. 2006 Sep;47(9):1915-27. Epub 2006 Jun 20 PubMed.
Kaminski WE, Orsó E, Diederich W, Klucken J, Drobnik W, Schmitz G. Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7). Biochem Biophys Res Commun. 2000 Jul 5;273(2):532-8. PubMed.
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University of British Columbia
Steinberg and colleagues provide new compelling evidence for the genetic association between loss-of-function variants in the lipid transporter ABCA7 and increased risk of Alzheimer’s disease. Whole-genome sequences of 2,636 Icelanders were imputed into 104,220 long-ranged phased individuals and association testing was performed with 3,419 people with AD and 151,805 population controls. The most significant association, for both loss-of-function and missense variants, was for ABCA7, which had a combined odds ratio of 2.12 (p=2.2 x 10-13), and is distinct from the common variant previously reported to be associated with AD risk. Intriguingly, there was no evidence of interaction of AD-associated alleles of either APOE or TREM2.
How ABCA7 contributes to AD risk is not yet entirely understood, and this now becomes a critically important question. ABCA7 is a member of the A subclass of ATP-binding cassette transporters that function to transport lipids across cellular membranes (Kim et al., 2008). ABCA7 is highly expressed in the central nervous system, and is particularly abundant in microglia. In cellular models, ABCA7 can function to promote cholesterol and phospholipid efflux to either ApoE or ApoA-I lipid acceptors, leading to hypotheses regarding its potential role in lipoprotein biogenesis. However, the ancestral role of ABCA7 may be more aligned with a role in regulating phagocytic activity. Evidence supporting this function includes in vitro studies showing that ABCA7 can promote phagocytosis in cell lines, and that ced7, a functional orthologue of ABCA7 in C. elegans, is essential for engulfment of apoptotic cells (Iwamoto et al. 2006; Jehle et al., 2006). Intriguingly, ABCA7 has been shown to preferentially flip phosphatidylserine from the cytoplasmic to the exocytoplasmic leaflet of membranes in an energy-dependent manner (Quazi and Molday, 2013), raising the hypothesis that ABCA7 may contribute to the presentation of “eat-me” signals in cells destined for engulfment.
Regulation of the innate immune system is intimately regulated with that of lipid metabolism, particularly for professional phagocytes that ingest lipid-rich debris. Lipidomic approaches have begun to reveal distinct lipid mediator signatures in human phagocytes, which may influence both lipid trafficking and phagocytic activities across the M1-M2 macrophage activation spectrum (Dalli and Serhan, 2012; Chinetti-Gbaquidi et al., 2011).
The increasing evidence that genetic variants in ABCA7 contribute to the risk of AD raises several important questions for future studies. Understanding the mechanisms by which ABCA7 in relevant cell types regulates phagocytic clearance of damaged cells is clearly a high-priority area. It will also be important to determine whether ABCA7 activity contributes to clearance of cellular debris after acute brain insult.
References:
Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem. 2008 Mar;104(5):1145-66. PubMed.
Iwamoto N, Abe-Dohmae S, Sato R, Yokoyama S. ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis. J Lipid Res. 2006 Sep;47(9):1915-27. Epub 2006 Jun 20 PubMed.
Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, Vandivier RW, Wang N, Greenberg S, Dale BM, Qin C, Henson PM, Tall AR. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol. 2006 Aug 14;174(4):547-56. PubMed.
Quazi F, Molday RS. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J Biol Chem. 2013 Nov 29;288(48):34414-26. Epub 2013 Oct 4 PubMed.
Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012 Oct 11;120(15):e60-72. Epub 2012 Aug 17 PubMed.
Chinetti-Gbaguidi G, Baron M, Bouhlel MA, Vanhoutte J, Copin C, Sebti Y, Derudas B, Mayi T, Bories G, Tailleux A, Haulon S, Zawadzki C, Jude B, Staels B. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res. 2011 Apr 15;108(8):985-95. Epub 2011 Feb 24 PubMed.
Sanders-Brown Center on Aging, University of Kentucky
First, these data essentially confirm the common ABCA7 GWAS SNP as a legitimate genetic risk for Alzheimer's disease. Overall, this story is a nice integration of the rare variant/robust risk and common variant/modest risk thought process. SNPs with large effects on complex human disease are likely to be of two kinds: rare SNPs with large impact, or common SNPs with modest impact. ABCA7 now has examples of both types.
Second, the data support the role of microglia in AD because ABCA7 has been linked with phagocytosis (Jehle et al., 2006; Kim et al., 2013; Tanaka et al., 2011). The alternative ABCA7 mechanism involves lipid transport, but the more compelling data support phagocytosis. That said, there are macrophage data that ABCA7 moves into the membrane forming the phagocytic cup (Jehle et al., 2006); perhaps ABCA7 functions to transport lipids to help form this cup. Overall, the result here that loss of ABCA7 increases AD risk fits nicely with the emerging role of microglia in AD.
Third, the question of what this paper means for AD treatment and/or prevention arises. The odds ratio will put ABCA7 on the pharmacology map. The approach, though, is a bit more nebulous, because it’s harder to activate a protein than to inhibit it. That said, based on the idea that more ABCA7 is helpful, there are reports that statins, for example, can increase ABCA7 (Tanaka et al., 2011), so this could help resurrect statins as AD therapeutics.
References:
Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, Vandivier RW, Wang N, Greenberg S, Dale BM, Qin C, Henson PM, Tall AR. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol. 2006 Aug 14;174(4):547-56. PubMed.
Kim WS, Li H, Ruberu K, Chan S, Elliott DA, Low JK, Cheng D, Karl T, Garner B. Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer's disease. J Neurosci. 2013 Mar 6;33(10):4387-94. PubMed.
Tanaka N, Abe-Dohmae S, Iwamoto N, Fitzgerald ML, Yokoyama S. HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7. Atherosclerosis. 2011 Aug;217(2):407-14. Epub 2011 Jun 23 PubMed.
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