ABCA1 p.Met671Leu
| Predicted by SNAP2: | A: D (80%), C: D (71%), D: D (91%), E: D (91%), F: D (80%), G: D (91%), H: D (91%), I: D (75%), K: D (91%), L: N (53%), N: D (91%), P: D (95%), Q: D (75%), R: D (91%), S: D (91%), T: D (85%), V: D (59%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] MiR-106b impairs cholesterol efflux and increases ... Exp Neurol. 2012 Jun;235(2):476-83. Epub 2011 Nov 18. Kim J, Yoon H, Ramirez CM, Lee SM, Hoe HS, Fernandez-Hernando C, Kim J
MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression.
Exp Neurol. 2012 Jun;235(2):476-83. Epub 2011 Nov 18., [PMID:22119192]
Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) is a cholesterol transporter that transfers excess cellular cholesterol onto lipid-poor apolipoproteins. Given its critical role in cholesterol homeostasis, ABCA1 has been studied as a therapeutic target for Alzheimer's disease. Transcriptional regulation of ABCA1 by liver X receptor has been well characterized. However, whether ABCA1 expression is regulated at the posttranscriptional level is largely unknown. Identification of a novel pathway that regulates ABCA1 expression may provide new strategy for regulating cholesterol metabolism and amyloid beta (Abeta) levels. Since ABCA1 has an unusually long 3' untranslated region, we investigated whether microRNAs could regulate ABCA1 expression. We identified miR-106b as a novel regulator of ABCA1 expression and Abeta metabolism. miR-106b significantly decreased ABCA1 levels and impaired cellular cholesterol efflux in neuronal cells. Furthermore, miR-106b dramatically increased levels of secreted Abeta by increasing Abeta production and preventing Abeta clearance. Alterations in Abeta production and clearance were rescued by expression of miR-106b-resistant ABCA1. Taken together, our data suggest that miR-106b affects Abeta metabolism by suppressing ABCA1 expression.
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41 pcDNA3.1- mouse ABCA1 open reading frame (ORF) without 3' untranslated region (UTR) and pAG3-Swedish mutant (K670N/M671L) APPsw ORF without 3' UTR were kind gifts from Dr. David M. Holtzman (Washington University, St. Louis, USA) and Dr. Todd Golde (University of Florida, Gainesville, USA), respectively.
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ABCA1 p.Met671Leu 22119192:41:115
status: NEW70 Measurement of secreted Aβ levels Neuro2a cells were plated at a density of 1.25×105 cells/well in a 24-well plate 1 day before transfection. Neuro2A cells were first transfected with 0.3 μg of pAG3-Swedish mutant (K670N/M671L) APPsw ORF without 3' UTR for 8 h and allowed to recover overnight. Then, miR-106b or a scrambled negative control was transfected into cells.
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ABCA1 p.Met671Leu 22119192:70:235
status: NEW[hide] Memory deficits in APP23/Abca1+/- mice correlate w... ASN Neuro. 2009 Apr 30;1(2). pii: e00006. doi: 10.1042/AN20090015. Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R
Memory deficits in APP23/Abca1+/- mice correlate with the level of Abeta oligomers.
ASN Neuro. 2009 Apr 30;1(2). pii: e00006. doi: 10.1042/AN20090015., [PMID:19570031]
Abstract [show]
ABCA1, a member of the ATP-binding cassette family of transporters, lipidates ApoE (apolipoprotein A) and is essential for the generation of HDL (high-density lipoprotein)-like particles in the CNS (central nervous system). Lack of Abca1 increases amyloid deposition in several AD (Alzheimer's disease) mouse models. We hypothesized that deletion of only one copy of Abca1 in APP23 (where APP is amyloid precursor protein) AD model mice will aggravate memory deficits in these mice. Using the Morris Water Maze, we demonstrate that 2-year-old Abca1 heterozygous APP23 mice (referred to as APP23/het) have impaired learning during acquisition, and impaired memory retention during the probe trial when compared with age-matched wild-type mice (referred to as APP23/wt). As in our previous studies, the levels of ApoE in APP23/het mice were decreased, but the differences in the levels of Abeta and thioflavin-S-positive plaques between both groups were insignificant. Importantly, dot blot analysis demonstrated that APP23/het mice have a significantly higher level of soluble A11-positive Abeta (amyloid beta protein) oligomers compared with APP23/wt which correlated negatively with cognitive performance. To confirm this finding, we performed immunohistochemistry with the A11 antibody, which revealed a significant increase of A11-positive oligomer structures in the CA1 region of hippocampi of APP23/het. This characteristic region-specific pattern of A11 staining was age-dependent and was missing in younger APP23 mice lacking Abca1. In contrast, the levels of Abeta*56, as well as other low-molecular-mass Abeta oligomers, were unchanged among the groups. Overall, the results of the present study demonstrate that in aged APP23 mice memory deficits depend on Abca1 and are likely to be mediated by the amount of Abeta oligomers deposited in the hippocampus.
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33 APP23 transgenic mice express the human familial AD mutant APP751 with Swedish double mutations at positions 670/671 (APPK670N, M671L) (Sturchler-Pierrat et al., 1997).
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ABCA1 p.Met671Leu 19570031:33:128
status: NEW32 APP23 transgenic mice express the human familial AD mutant APP751 with Swedish double mutations at positions 670/671 (APPK670N, M671L) (Sturchler-Pierrat et al., 1997).
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ABCA1 p.Met671Leu 19570031:32:128
status: NEW[hide] Lack of ABCA1 considerably decreases brain ApoE le... J Biol Chem. 2005 Dec 30;280(52):43224-35. Epub 2005 Oct 5. Koldamova R, Staufenbiel M, Lefterov I
Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice.
J Biol Chem. 2005 Dec 30;280(52):43224-35. Epub 2005 Oct 5., [PMID:16207713]
Abstract [show]
ABCA1 (ATP-binding cassette transporter A1) is a major regulator of cholesterol efflux and high density lipoprotein (HDL) metabolism. Mutations in human ABCA1 cause severe HDL deficiencies characterized by the virtual absence of apoA-I and HDL and prevalent atherosclerosis. Recently, it has been reported that the lack of ABCA1 causes a significant reduction of apoE protein level in the brain of ABCA1 knock-out (ABCA1-/-) mice. ApoE isoforms strongly affect Alzheimer disease (AD) pathology and risk. To determine further the effect of ABCA1 on amyloid deposition, we used APP23 transgenic mice in which the human familial Swedish AD mutant is expressed only in neurons. We demonstrated that the targeted disruption of ABCA1 increases amyloid deposition in APP23 mice, and the effect is manifested by an increased level of Abeta immunoreactivity, as well as thioflavine S-positive plaques in brain parenchyma. We found that the lack of ABCA1 also considerably increased the level of cerebral amyloid angiopathy and exacerbated cerebral amyloid angiopathy-related microhemorrhage in APP23/ABCA1-/- mice. Remarkably, the elevation in parenchymal and vascular amyloid in APP23/ABCA1-/- mice was accompanied by a dramatic decrease in the level of soluble brain apoE, although insoluble apoE was not changed. The elevation of insoluble Abeta fraction in old APP23/ABCA1-/- mice, accompanied by a lack of changes in APP processing and soluble beta-amyloid in young APP23/ABCA1-/- animals, supports the conclusion that the ABCA1 deficiency increases amyloid deposition. These results suggest that ABCA1 plays a role in the pathogenesis of parenchymal and cerebrovascular amyloid pathology and thus may be considered a therapeutic target in AD.
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27 We used APP23 transgenic mice expressing human familial AD mutant APP751 with Swedish double mutation at positions 670/671 (APPK670N, M671L) (23).
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ABCA1 p.Met671Leu 16207713:27:134
status: NEW