Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
J Neurosci. 2012 May 9;32(19):6490-500. doi: 10.1523/JNEUROSCI.0630-12.2012.
Accumulation of β-amyloid (Aβ) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of AD patients and mice models of AD suggested that cholesterol homeostasis is altered in neurons that accumulate Aβ. Here we directly investigated the role of intracellular oligomeric Aβ(42) (oAβ(42)) in neuronal cholesterol homeostasis. We report that oAβ(42) induces cholesterol sequestration without increasing cellular cholesterol mass. Several features of AD, such as endosomal abnormalities, brain accumulation of Aβ and neurofibrillary tangles, and influence of apolipoprotein E genotype, are also present in Niemann-Pick type C, a disease characterized by impairment of intracellular cholesterol trafficking. These common features and data presented here suggest that a pathological mechanism involving abnormal cholesterol trafficking could take place in AD. Cholesterol sequestration in Aβ-treated neurons results from impairment of intracellular cholesterol trafficking secondary to inhibition of protein prenylation. oAβ(42) reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism of oAβ(42)-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ(42)-treated neurons recovers normal protein prenylation, reduces cholesterol sequestration, and prevents Aβ-induced neurotoxicity. Significant to AD, reduced levels of protein prenylation are present in the cerebral cortex of the TgCRND8 mouse model. In conclusion, we demonstrate a significant inhibitory effect of Aβ on protein prenylation and identify SREBP-2 as a target of oAβ(42), directly linking Aβ to cholesterol homeostasis impairment.
β-淀粉样蛋白（Aβ）在脑神经元内的积累是阿尔茨海默病（AD）的早期和关键事件。AD 患者大脑和 AD 小鼠模型的研究表明，在积累 Aβ的神经元中胆固醇稳态发生改变。在这里，我们直接研究了细胞内寡聚体 Aβ（42）（oAβ（42））在神经元胆固醇稳态中的作用。我们报告说，oAβ（42）诱导胆固醇隔离，而不增加细胞内胆固醇质量。AD 的几个特征，如内体异常、大脑中 Aβ的积累和神经原纤维缠结，以及载脂蛋白 E 基因型的影响，也存在于尼曼-匹克 C 型中，这是一种以细胞内胆固醇运输受损为特征的疾病。这些共同特征和这里呈现的数据表明，涉及异常胆固醇运输的病理机制可能发生在 AD 中。Aβ 处理神经元中的胆固醇隔离是由于蛋白质异戊烯化抑制导致的细胞内胆固醇运输受损所致。oAβ（42）减少固醇调节元件结合蛋白-2（SREBP-2）切割，导致蛋白质异戊烯化减少。oAβ（42）诱导的神经元死亡的机制是蛋白质异戊烯化的抑制。将异戊烯基焦磷酸供给 oAβ（42）处理的神经元可恢复正常的蛋白质异戊烯化，减少胆固醇隔离，并防止 Aβ 诱导的神经毒性。在 TgCRND8 小鼠模型的大脑皮层中存在蛋白质异戊烯化的显著减少，这对 AD 具有重要意义。总之，我们证明了 Aβ 对蛋白质异戊烯化具有显著的抑制作用，并确定 SREBP-2 是 oAβ（42）的靶标，直接将 Aβ 与胆固醇稳态受损联系起来。
