ABCG1 and ABCG4 Suppress γ-Secretase Activity and Amyloid β Production

ATP-binding cassette G1 (ABCG1) and ABCG4, expressed in neurons and glia in the central nervous system, mediate cholesterol efflux to lipid acceptors. The relationship between cholesterol level in the central nervous system and Alzheimer’s disease has been reported. In this study, we examined the effects of ABCG1 and ABCG4 on amyloid precursor protein (APP) processing, the product of which, amyloid β (Aβ), is involved in the pathogenesis of Alzheimer’s disease. Expression of ABCG1 or ABCG4 in human embryonic kidney 293 cells that stably expressed Swedish-type mutant APP increased cellular and cell surface APP levels. Products of cleavage from APP by α-secretase and by β-secretase also increased. The levels of secreted Aβ, however, decreased in the presence of ABCG1 and ABCG4, but not ABCG4-KM, a nonfunctional Walker-A lysine mutant. In contrast, secreted Aβ levels increased in differentiated SH-SY5Y neuron-like cells in which ABCG1 and ABCG4 were suppressed. Furthermore, Aβ42 peptide in the cerebrospinal fluid from Abcg1 null mice significantly increased compared to the wild type mice. To examine the underlying mechanism, we analyzed the activity and distribution of γ-secretase. ABCG1 and ABCG4 suppressed γ-secretase activity and disturbed γ-secretase localization in the raft domains where γ-secretase functions. These results suggest that ABCG1 and ABCG4 alter the distribution of γ-secretase on the plasma membrane, leading to the decreased γ-secretase activity and suppressed Aβ secretion. ABCG1 and ABCG4 may inhibit the development of Alzheimer’s disease and can be targets for the treatment of Alzheimer’s disease.

ATP结合盒转运蛋白G1（ATP-binding cassette G1，ABCG1）与ABCG4在中枢神经系统的神经元和神经胶质细胞中表达，可介导胆固醇向脂质受体的外流。已有研究证实中枢神经系统胆固醇水平与阿尔茨海默病（Alzheimer’s disease）存在关联。本研究探讨了ABCG1与ABCG4对淀粉样前体蛋白（amyloid precursor protein，APP）加工过程的影响——APP的剪切产物淀粉样β蛋白（amyloid β，Aβ）参与阿尔茨海默病的发病机制。我们在稳定表达瑞典突变型APP的人胚肾293细胞中过表达ABCG1或ABCG4，结果发现细胞内及细胞表面的APP水平均升高；α分泌酶与β分泌酶对APP的剪切产物水平也同步上升。然而，当存在ABCG1与ABCG4时，分泌型Aβ的水平反而下降，而该效应在非功能性Walker-A赖氨酸突变体ABCG4-KM组中并未出现。与之相反，在ABCG1与ABCG4表达被抑制的分化型SH-SY5Y神经元样细胞中，分泌型Aβ的水平则升高。此外，与野生型小鼠相比，Abcg1基因敲除小鼠脑脊液中的Aβ42肽水平显著升高。为探究潜在的分子机制，我们分析了γ分泌酶（γ-secretase）的活性与分布情况。结果显示，ABCG1与ABCG4可抑制γ分泌酶的活性，并干扰其在发挥功能的脂筏结构域中的定位。上述结果表明，ABCG1与ABCG4可改变γ分泌酶在质膜上的分布，进而降低其酶活性并抑制Aβ的分泌。ABCG1与ABCG4或可抑制阿尔茨海默病的发生发展，有望成为阿尔茨海默病治疗的潜在靶点。