Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
J Neurosci Res. 2010 Jul;88(9):1985-94. doi: 10.1002/jnr.22360.
Amyloid beta (Abeta) is a key molecule in the pathogenesis of Alzheimer's disease, but its physiological function remains unclear. Abeta is produced from amyloid precursor protein (APP) by beta- and gamma-secretases, which is enhanced by high levels of cellular cholesterol, so cholesterol is a risk factor for Alzheimer's disease. This linkage led us to hypothesize that Abeta is produced to regulate cellular cholesterol levels in response to high-cholesterol stimulation. Here we show that Abeta production caused a reduction of cellular cholesterol levels in transfected HEK293 cells and neuronal IMR-32 and Neuro2a cells, which was accompanied by an increase in efflux of cholesterol from cells. Fractionation of the culture media by ultracentrifugation and subsequent immunoelectron microscopic observation revealed that Abeta assembled high-density lipoprotein-like particles with cellular cholesterol during its secretion. This assembly was mediated by the ATP-binding cassette transporter A1. APP transgenic and knockout mice exhibited lower and higher levels of cellular cholesterol in their brains, suggesting that Abeta-mediated regulation of cellular cholesterol is physiological. Furthermore, we found that, when injected into mouse cerebral ventricle, reconstituted lipoproteins with Abeta were excreted into the peripheral tissues more efficiently than those without Abeta. This result suggests that Abeta mediates cholesterol transport from the brain to the circulation. We propose, based on these findings, a novel, apolipoprotein-like function for Abeta that is involved in maintenance of cellular and cerebral cholesterol homeostasis.
淀粉样蛋白 β（Abeta）是阿尔茨海默病发病机制中的关键分子，但它的生理功能仍不清楚。Abeta 由淀粉样前体蛋白（APP）通过β-和γ-分泌酶产生，其产生受到细胞胆固醇水平升高的增强，因此胆固醇是阿尔茨海默病的一个风险因素。这种联系使我们假设 Abeta 的产生是为了在高胆固醇刺激下调节细胞胆固醇水平。在这里，我们表明 Abeta 的产生导致转染的 HEK293 细胞和神经元 IMR-32 和 Neuro2a 细胞中的细胞胆固醇水平降低，这伴随着胆固醇从细胞中的流出增加。通过超速离心对培养物进行分级，并随后进行免疫电子显微镜观察，发现在其分泌过程中 Abeta 与细胞胆固醇组装成高密度脂蛋白样颗粒。这种组装是由 ATP 结合盒转运蛋白 A1 介导的。APP 转基因和敲除小鼠的大脑中的细胞胆固醇水平较低和较高，这表明 Abeta 介导的细胞胆固醇调节是生理性的。此外，我们发现，当将重组脂蛋白注入小鼠脑室时，含有 Abeta 的脂蛋白比不含 Abeta 的脂蛋白更有效地被排泄到外周组织中。这一结果表明 Abeta 介导了胆固醇从大脑到循环的运输。基于这些发现，我们提出了 Abeta 的一种新的、载脂蛋白样功能，该功能参与维持细胞和大脑胆固醇的动态平衡。
