中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2420-2421.doi: 10.4103/1673-5374.313044

• 观点:退行性病与再生 • 上一篇    下一篇

用Posiphen进行的先期探索以规范唐氏综合征中的淀粉样前体蛋白

  

  • 出版日期:2021-12-15 发布日期:2021-05-14

A pilot exploration with Posiphen to normalize amyloid precursor protein in Down syndrome

Xu-Qiao Chen*   

  1. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
  • Online:2021-12-15 Published:2021-05-14
  • Contact: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
  • Supported by:
    The author thanks Professor William C. Mobley (Department of Neurosciences, University of California San Diego) for guidance and all the colleagues contributing to this project.

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摘要：

Neural Regen Res：淀粉样前体蛋白靶向策略：从Posiphen开始

   基于对淀粉样前体蛋白在唐氏综合征型阿尔茨海默病发病机制中作用的临床前研究，可以设想一些策略。淀粉样前体蛋白的表达可以在mRNA或蛋白水平上进行调节。我们开始验证我们的假设，即正常化淀粉样前体蛋白基因剂量可以拯救Ts65Dn小鼠中与阿尔茨海默病相关的内体表型。Posiphen是一种口服小分子，靶向包括淀粉样前体蛋白在内的多种蛋白质的mRNA中的保守调控元件（铁反应元件干环），并减少其翻译。在阿尔茨海默病的APP/PS1小鼠模型中，Posiphen降低了淀粉样前体蛋白及其相关产物的水平，并使空间工作记忆、情境恐惧学习和突触功能得到改善。在I期临床试验中，Posiphen被证明具有良好的耐受性，并可使轻度认知障碍受试者脑脊液中可溶性淀粉样前体蛋白片段和tau物种水平的降低。

    来自美国加州大学圣地亚哥分校的Xu-Qiao Chen团队发现在体外，Posiphen以翻译依赖的方式降低了淀粉样前体蛋白水平，逆转了Rab5过度激活和早期内体增大，恢复了Ts65Dn原代神经元神经营养素信号的逆行轴突运输。在体内，对16个月大的Ts65Dn小鼠进行Posiphen治疗（50 mg/kg/d，26天，腹腔内给药）也具有良好的耐受性，并诱导aβ42水平的减少，Rab5活性降低，磷酸化tau，更重要的是逆转了原肌球蛋白受体激酶B/丝裂原活化蛋白激酶/cAMP反应元件结合蛋白信号通路的激活缺陷。Posiphen不仅降低了Ts65Dn小鼠的APP/CTF/Aβ42，而且降低了磷酸化tau的水平。与阿尔茨海默病一样，唐氏综合征也会在不同的阶段发展出不同的神经病变，包括炎症，因此在临床前研究和临床试验中都可以考虑针对不同病理学的联合治疗来对抗唐氏综合征中的阿尔茨海默病。

    文章在《中国神经再生研究（英文版）》杂志2021年 12 月 12  期发表。

    https://orcid.org/0000-0001-9799-7246(Xu-Qiao Chen)

Abstract: DS is the most common cause of Alzheimer’s disease (AD) and has a known AD-causing genetic variation which is trisomy of the whole or part of Homo sapiens chromosome 21 (HSA21) (Chen and Mobley, 2019a). Compared with AD, DS usually present with various symptoms and manifestations which are related to dysfunction of multiple body systems; the extra copies of the many genes present in HSA21 in DS can cause various developmental problems including neurodevelopmental deficits, which underlie the physical features in DS and may also contribute to the AD-related neurological symptoms of DS like cognition decline (Antonarakis et al., 2020). However, DS and AD share many pathological hallmarks including amyloid plaques and neurofibrillary tangles, synaptic and neuronal loss, dysregulation of endosomal pathway and others (Chen and Mobley, 2019a). The plaques and tangles have been studied extensively, while the dysfunction of early endosome has been found to be impacted long before appearance of amyloid deposits and neurofibrillary tangles with amyloid beta (Aβ) of varing length and phosphorylated tau as the main components, respectively (Nixon, 2017; Chen and Mobley, 2019a). Deficient endosome-mediated retrograde axonal transport of neurotrophic signals plays an important role in the neuropathogenesis in both DS and AD as continuing neurotrophic support is required for maintenance of mature neurons including the basal forebrain cholinergic neurons (BFCNs) whose degeneration has been linked to age-related cognitive dysfunction in DS and AD (Chen and Mobley, 2019b). HSA21 contains about 233 protein-coding genes with several encoding protein products demonstrated to contribute to different phenotypes in DS (Antonarakis et al., 2020) from the extensive researches in the different mouse models of DS, including Ts65Dn mouse which are segmentally trisomic for orthologs of about half of the protein coding genes located on HSA21 (Antonarakis et al., 2020). Accumulated evidence have attributed AD pathogenesis to toxic oligomeric Aβ and tau (Chen and Mobley, 2019a), however, recent clinical trials intending to target them in AD have yet to demonstrate considerable efficacy. Importantly, the 99 amino acid C-terminal fragment (β-CTF) of amyloid precursor protein (APP) was recently found to dysregulate endosomal and lysosomal systems as well as induce cholinergic neurodegeneration in an Aβ-independent manner (Xu et al., 2016; Nixon, 2017; Chen and Mobley, 2019b). Thus, reviewing the hypotheses for AD and discovering novel targets will be beneficial to combat AD and AD in DS.