Department of Molecular Genetics, Center for Alzheimer's and Neurodegenerative Disease, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. doi: 10.1073/pnas.0914984107. Epub 2010 Jun 14.
Apolipoprotein E (ApoE) genotype is a powerful genetic modifier of Alzheimer's disease (AD). The ApoE4 isoform significantly reduces the mean age-of-onset of dementia through unknown mechanisms. Here, we show that ApoE4 selectively impairs synaptic plasticity and NMDA receptor phosphorylation by Reelin, a regulator of brain development and modulator of synaptic strength. ApoE4 reduces neuronal surface expression of Apoer2, a dual function receptor for ApoE and for Reelin, as well as NMDA and AMPA receptors by sequestration in intracellular compartments, thereby critically reducing the ability of Reelin to enhance synaptic glutamate receptor activity. As a result, the ability of Reelin to prevent LTP suppression by extracts from AD-afflicted human brains in hippocampal slices from knockin mice expressing the human ApoE4 isoform is severely impaired. These findings show an isoform-specific role of ApoE in the localization and intracellular trafficking of lipoprotein and glutamate receptors and thereby reveal an alternative mechanism by which ApoE4 may accelerate onset of dementia and neuronal degeneration by differentially impairing the maintenance of synaptic stability.
载脂蛋白 E（ApoE）基因型是阿尔茨海默病（AD）的一个强大遗传修饰因子。ApoE4 同工型通过未知机制显著降低痴呆的平均发病年龄。在这里，我们表明 ApoE4 通过 Reelin 选择性地损害突触可塑性和 NMDA 受体磷酸化，Reelin 是大脑发育的调节剂和突触强度的调节剂。ApoE4 通过隔离在细胞内隔室中，减少神经元表面表达 Apoer2，Apoer2 是 ApoE 和 Reelin 的双重功能受体，以及 NMDA 和 AMPA 受体，从而严重降低 Reelin 增强突触谷氨酸受体活性的能力。结果，Reelin 防止来自表达人类 ApoE4 同工型的 knockin 小鼠海马切片中 AD 受累人脑提取物抑制 LTP 的能力严重受损。这些发现表明 ApoE 在脂蛋白和谷氨酸受体的定位和细胞内运输中具有同工型特异性作用，从而揭示了 ApoE4 通过差异损害突触稳定性的维持来加速痴呆和神经元变性发作的另一种机制。
