Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2018 Oct 30;7:e40048. doi: 10.7554/eLife.40048.
ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer's disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification. We found that pharmacological and genetic inhibition of NHE6, the primary proton leak channel in the early endosome, in rodents completely reverses the ApoE4-induced recycling block of the ApoE receptor Apoer2/Lrp8 and the AMPA- and NMDA-type glutamate receptors that are regulated by, and co-endocytosed in a complex with, Apoer2. Moreover, NHE6 inhibition restores the Reelin-mediated modulation of excitatory synapses that is impaired by ApoE4. Our findings suggest a novel potential approach for the prevention of late-onset AD.
载脂蛋白 E4（ApoE4）基因型是晚发性阿尔茨海默病（AD）最常见也是最重要的临床危险因素。现有证据表明，这种风险增加的根本原因是早期内体水平的运输缺陷。ApoE4 与最常见的 ApoE3 同工型仅在一个氨基酸上有所不同，该氨基酸增加了其等电点，并促进 ApoE4 在内涵体小泡酸化时展开。我们发现，在啮齿动物中，通过药理学和遗传学抑制早期内涵体中的主要质子泄漏通道 NHE6，可完全逆转 ApoE4 诱导的 ApoE 受体 Apoer2/Lrp8 的再循环阻断，以及受 Apoer2 调节并与之共内吞的 AMPA 和 NMDA 型谷氨酸受体。此外，NHE6 抑制可恢复 ApoE4 损害的 Reelin 介导的兴奋性突触调节。我们的研究结果表明，这为预防晚发性 AD 提供了一种新的潜在方法。
