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The ATP-binding cassette, sub-family A (ABC1), member 7 (ABCA7) gene was first discovered in human macrophages and is abundantly expressed in bone marrow cells, mainly monocytes and granulocytes. In situ hybridization experiments showed that ABCA7 was highly expressed in the neurons of adult rats, especially in the hippocampal CA1 region. The study found that ABCA7 mRNA expression in microglia is 10 times higher than in neurons. The human ABCA7 gene encodes a polypeptide molecule of 2,146 amino acids with a molecular mass of 220 KDa. This polypeptide molecule is a molecular transporter that contains two highly conserved cytoplasmic ATP-binding cassettes and two transmembrane domains that are responsible for transporting lipids and other lipoprotein molecules across the cell membrane.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurofibrillary tangles and senile plaques in the brain. The clinical manifestations are progressive cognitive decline and eventually development of dementia. The deposition of amyloid β (Aβ) in the central nervous system to form senile plaques is the core event of AD. Abnormal cholesterol metabolism plays an important role in the development of AD and the production of Aβ. ABCA7, like members of other ABC families, is involved in lipid metabolism and plays an important role in the development of AD.
The Effect of ABCA7 and Blood Lipids
Serum high fat and high cholesterol levels are risk factors for the onset of AD. Serum total cholesterol levels are positively correlated with the prevalence of AD and mild cognitive impairment. Elevated serum cholesterol levels can increase the risk of AD by more than 3 times. At present, the lipid transport of ABCA7 is still unclear. ABCA7 is the closest homologue of ABCA1 (the two amino acids are 54% identical). It is predicted that ABCA7 will strongly stimulate the secretion of intracellular cholesterol to apoE and apoA-I which has not yet bound lipids. ABCA7 promotes lipid excretion in hematopoietic cells, especially in macrophages. However, studies have found that the expression of ABCA7 promotes the outflow of phospholipids including lecithin and sphingomyelin, and does not effectively promote cholesterol efflux. Unlike expected, ABCA7 was isolated from macrophages and the mice exhibited normal cholesterol and lecithin release, suggesting that ABCA7 may have a different biological function. Therefore, how ABCA7 affects lipid metabolism in AD patients requires more in-depth studies to confirm.
Figure 1. Possible pathogenic pathways mediated by ABCA7 in AD. (Aikawa, et al. 2018).
ABCA7 and Aβ
Aβ plays an important role in the pathological mechanism of AD. It is not only the starting substance and main structural substance of senile plaque, but also toxic to nerve cells, so it is considered to be an early trigger for AD. Aβ is derived from an amyloid transmembrane precursor protein (APP) by proteolytic enzyme β and γ, mainly including Aβ40 and Aβ42. Steinberg et al found that (APP) gene, presenilin 1 (PS1) gene, and premature 2 (PS2) gene mutations lead to the development of early-onset familial AD. The ABCA7 gene is one of the susceptible genes of a delayed-onset AD, and its loss of function will significantly increase the risk of disease. ABCA7 promotes cholesterol efflux and inhibits Aβ secretion, and enhances the function of macrophage apoptotic cells through the C1q complement pathway. Studies by Vasquez et al have shown that ABCA7 expression reduces the risk of AD by enhancing the action of phagocytosis of Aβ, apoptotic cells, and synthetic substrates. ABCA7 reduces the risk of AD by removing Aβ deposits.
Recently, it has been found that knocking out the ABCA7 gene in the AD rat model increases the Aβ plaque deposit in the hippocampus of the brain by 53%. Hughes et al. found that the ABCA7rs3764650 polymorphism was significantly associated with Aβ plaques by PET imaging. In the model of knockout of ABCA7, phagocytic cells aggregate Aβ into dimers or trimers, suggesting that knockdown of the ABCA7 gene attenuates the ability to clear Aβ. Knocking out ABCA7 will alter the blood lipid levels in the mouse brain and impair memory. Sakae et al. found in the cultured amyloid APP/PS1 mouse model that the absence of ABCA7 accelerated the formation of plaque burden. Its mechanism may be to promote the decomposition of APP into Aβ by increasing the level of β-secretase, but it does not affect the clearance of Aβ.
ABCA7 Common Site Variation and AD
Recently, it has been reported that the AD protective rs3764650 allele is associated with increased ABCA7 gene expression, and it is speculated that related SNPs can protect AD by increasing the expression of ABCA7. Liu et al.'s study on ABCA7 genotype and AD in Chinese Han people found that the ABCA7 genotype is closely related to a sporadic AD in Chinese Han people. The results were influenced by age and ApoE ε4 status, ie, ApoE ε4 carriers and age increased the risk associated with ABCA7 for sporadic AD. However, the LS3764650 minimal allele G was not significantly associated with AD. Studies have shown that ABCA7 rs3764650 and ApoEε4 have significant correlations in language learning and memory, working memory and transient memory. The expression of ABCA7 in different parts of the brain is weak.
Reitz et al. found a new ABCA7 SNP locus rs115550680 (OR=1.78) in a study of 5,896 African Americans over 60 years of age. A recent study of the Icelandic population showed that a rare loss of function in ABCA7 would increase the risk of AD (OR = 2.1), and in a second study of the same population, the association had an OR of 1.7. The variation of the locus rs200538373 resulted in the early termination of the codon. Therefore, it is speculated that the loss of ABCA7 function increases the risk of AD, and increasing the expression of ABCA7 is associated with a lower risk of AD. In a study of African Americans by Cukier et al., there was a high linkage disequilibrium between deletions of the ABCA7 risk allele, and ABCA7 deletions may exhibit ethnically specific pathogenic changes. However, ABCA7 expression was significantly higher in AD patients than in non-AD patients. Therefore, the expression of ABCA7 seems to be a compensatory mechanism.