脑内低密度脂蛋白受体的过度表达可显著抑制淀粉样沉积并增加细胞外 Aβ清除。
Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.
机构信息
Department of Neurology, Developmental Biology, Hope Center for Neurological Disorders, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
出版信息
Neuron. 2009 Dec 10;64(5):632-44. doi: 10.1016/j.neuron.2009.11.013.
Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-beta (A beta) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating A beta levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance A beta clearance, and decrease A beta deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50%-90%. Furthermore, LDLR overexpression dramatically reduced A beta aggregation and enhanced A beta clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.
载脂蛋白 E（APOE）是阿尔茨海默病（AD）最强的遗传风险因素。先前的研究表明，APOE 对淀粉样蛋白-β（Aβ）积累的影响在 AD 发病机制中起主要作用。因此，了解控制 APOE 代谢的蛋白质可能为调节 Aβ水平提供新的靶点。LDLR 是 LDL 受体家族的成员，与 APOE 结合，但它在 AD 发病机制中的潜在作用尚不清楚。我们假设大脑中 LDLR 的过表达会降低 APOE 水平，增强 Aβ清除，并减少 Aβ沉积。为了验证我们的假设，我们创建了几种在大脑中过表达 LDLR 的转基因小鼠，发现这些小鼠的 APOE 水平降低了 50%-90%。此外，LDLR 的过表达显著降低了 Aβ的聚集，并增强了 Aβ从脑细胞外空间的清除。载脂蛋白 E 转基因小鼠的斑块相关神经炎症反应减弱。这些发现表明，增加 LDLR 水平可能代表一种新的 AD 治疗策略。
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