Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
Tufts-AstraZeneca Laboratory for Basic and Translational Neuroscience, Boston, MA.
J Lipid Res. 2018 May;59(5):830-842. doi: 10.1194/jlr.M081851. Epub 2018 Mar 21.
apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.
载脂蛋白 E 是中枢神经系统内的主要脂质载体，也是迟发性阿尔茨海默病（AD）最强的遗传风险因素。载脂蛋白 E 主要通过 ABCA1 进行脂质化，两者均受核受体 X （LXR）的转录调控。来自 AD 小鼠模型的遗传（使用 ABCA1 过表达）和药理学（使用合成 LXR 激动剂）研究的大量证据表明，增加脂质化载脂蛋白 E 的水平可以改善认知表现，并且在某些品系中可以减少淀粉样蛋白负担。然而，直接的合成 LXR 配体具有肝毒性副作用，限制了它们的临床应用。在这里，我们描述了一组小分子，它们先前被注释为嘌呤能受体 P2X7 的拮抗剂，可增强 ABCA1 的表达和活性以及载脂蛋白 E 的分泌，并且不是直接的 LXR 配体。此外，P2X7 不是这些分子诱导 ABCA1 上调和载脂蛋白 E 分泌所必需的，这表明 ABCA1 和载脂蛋白 E 的作用机制独立于 P2X7 抑制。因此，我们已经确定了新型双重活性化合物，这些化合物通过间接的 LXR 机制上调 ABCA1 在多种中枢神经系统细胞类型中的表达，包括人星形胶质细胞、周细胞和小胶质细胞，并且独立地抑制 P2X7 受体活性。
