Department of Radiation Oncology, Taipei Medical University Hospital, Taipei, 110, Taiwan.
School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, 110, Taiwan.
Mol Neurobiol. 2019 Nov;56(11):7572-7582. doi: 10.1007/s12035-019-1587-1. Epub 2019 May 7.
A hallmark of Alzheimer's disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1-APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.
阿尔茨海默病（AD）发病机制的一个标志是细胞外斑块的积累，这些斑块主要由淀粉样前体蛋白（APP）裂解产生的淀粉样β（Aβ）组成。最近的报告表明，APP 与 huntingtin 相关蛋白-1（HAP1）一起在囊泡中的运输负调节 Aβ 的产生。在神经元中，HAP1 与 Abelson 辅助整合位点-1（AHI1）形成稳定复合物，其中突变导致神经发育和精神疾病。HAP1 和 AHI1 与原肌球蛋白受体激酶（Trk）相互作用，Trk 也与 APP 相关，并介导神经营养信号。在这项研究中，我们假设 AHI1 参与 APP 的运输和加工以挽救 AD 病理学。事实上，在表达人瑞典和印第安纳 APP 的小鼠神经母细胞瘤 N2a 细胞（设计为 AD 模型细胞）和 3xTg-AD 小鼠脑中，AHI1 显著减少。AD 模型细胞以及表达野生型 APP-695 的 Ahi1 敲低细胞的活力显著降低。此外，AD 模型细胞的神经突生长减少。AD 细胞裂解物和培养物中的 APP C 端片段-β（CTFβ）和 Aβ42 分别增加。为了研究 AHI1 改变 APP 活性的机制，我们在 AD 模型细胞中过表达人 AHI1。结果表明，尽管 APP 基因型不同，AHI1 仍在小鼠脑中与 APP 物理相互作用，并转染 N2a 细胞。AHI1 表达促进 APP 的细胞内易位，并抑制 APP 的淀粉样形成过程，从而降低 AD 模型细胞总裂解物中的 APP-CTFβ 水平以及培养物中的 Aβ 水平。因此，AHI1-APP 相互作用通过 Erk 激活增强神经营养信号，并导致细胞存活和分化恢复。
