Department of Experimental Medicine, University of Genoa, Genoa, Italy.
J Alzheimers Dis. 2011;25(4):645-53. doi: 10.3233/JAD-2011-110053.
Accumulating data supports the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-β (Aβ) peptides in the brain. Changes in the neuronal production of Aβ have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that Aβ may serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that Aβ(42) exerts an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Accordingly, we also show that ABCA1 expression is reduced in the brain of AβPP/PS1 transgenic mice. These results provide a biological function for Aβ peptides and may help to define the pathogenic relationship between cholesterol metabolism in brain and AD.
越来越多的数据支持胆固醇代谢的改变可能影响阿尔茨海默病（AD）的发展这一概念，AD 是一种神经退行性疾病，其特征是大脑中淀粉样β（Aβ）肽的进行性积累。神经元中 Aβ的产生变化被描述为胆固醇水平的函数，因此提示胆固醇动态平衡失调与 AD 发病机制之间存在因果关系。在生理条件下，血脑屏障有效地阻止了大脑中的胆固醇摄取，成熟神经元被认为依赖神经胶质细胞来提供胆固醇。在本研究中，我们检验了这样一个假设，即 Aβ 可能作为一种信号分子，能够将神经元对胆固醇的需求告知星形胶质细胞网络。总的来说，我们的数据支持了这一假设，并首次证明 Aβ（42）对培养的星形胶质细胞中胆固醇转运蛋白 ABCA1 的表达具有抑制作用。因此，我们还表明，AβPP/PS1 转基因小鼠大脑中的 ABCA1 表达减少。这些结果为 Aβ 肽提供了生物学功能，并可能有助于定义大脑中胆固醇代谢与 AD 之间的致病关系。
