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): 2417-2419.doi: 10.4103/1673-5374.313043

• 观点:退行性病与再生 • 上一篇    下一篇

短肽的长话：裂解特异性tau抗体的治疗功效

  

  • 出版日期:2021-12-15 发布日期:2021-05-14

A long story for a short peptide: therapeutic efficacy of a cleavage-specific tau antibody

Giuseppina Amadoro*, Valentina Latina, Pietro Calissano   

  1. Institute of Translational Pharmacology (IFT)–National Research Council (CNR), Via Fosso del Cavaliere 100, 00133-Rome, Italy (Amadoro G);European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161-Rome, Italy (Amadoro G, Latina V, Calissano P)
  • Online:2021-12-15 Published:2021-05-14
  • Contact: Amadoro Giuseppina, PhD, g.amadoro@inmm.cnr.it.
  • Supported by:
    The present work was supported by in part by Fondo Ordinario Enti (FOE D.M865/2019) in the framework of a collaboration agreement between the Italian National Research Council and EBRI (2019-2021) (to PC). VL was supported by Post-doctoral Fellowship by Operatori Sanitari Assistiti (OSA).

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摘要：

Neural Regen Res：抗体介导tau N末端结构域靶向是有价值治疗阿尔茨海默病的方法

    大部分针对aβ的药理学和免疫学方法（即分泌酶抑制剂和抗aβ抗体）未能达到阿尔茨海默病临床试验的最终终点，主要是由于出现毒性和/或缺乏疗效。因此，已经尝试了其他基于tau的干预措施，包括抑制激酶、靶向聚集、调节降解、微管稳定以及依赖抗体介导的细胞内和细胞外有害tau物种清除的被动或主动免疫治疗。与依靠直接刺激免疫反应产生抗体的主动免疫相比，被动免疫更安全，适应性更强，引起不良免疫反应的风险更低。tau抗体适合于特定靶向表位和/或其构象的选择，还具有成功穿透大脑结构的能力。tau抗体可以通过促进其从脑实质到外周脑脊液的净流出，沿着“外周”途径参与毒性tau物种的清除。前期试验证明tau抗体甚至可以穿过血脑屏障，并且很容易被神经元吸收，从而促进有毒形式tau的细胞内隔离和/或阻止其细胞外分泌并扩散到整个大脑。为了开发一种有效和安全的tau导向免疫疗法，分子特性的鉴定只是第一步。一种理想的抗体介导的治疗方法也应该提供对这些有害物种的特异性中和作用，同时避免因干扰正常生理形态的蛋白质而产生有害副作用。tau蛋白已经被认为是处理神经元的许多重要功能超出了微管稳定性和动力学的控制。

     来自意大利国家研究委员会的Amadoro Giuseppina团队首先鉴定并深入表征了一个分子量为20-22 kDa的片段，该片段是由位于人类最长tau异构体N末端的D25和R230氨基酸的异常截断产生的。通过一系列全面的生化、形态学和功能分析，发现这种短肽（又称NH2htau）具有强大的“功能增益”作用。建议早期的医疗方案，采用非侵入性和安全的联合疗法，旨在恢复APP/Aβ和tau的内稳态，例如h12A12mAb可能提供的内稳态，可能会显著增加阿尔茨海默病的临床管理，在老龄化社会中，阿尔茨海默病的快速增长将在2050年达到1.5亿以上。最后，由于视网膜和其他与中枢神经系统具有相似特征的眼部结构被认为是“通向大脑的窗口”，因此h12A12mAb也应被视为潜在的候选工具，以促进从患者眼睛检查开始的脑损伤的早期阿尔茨海默病诊断。

    文章在《中国神经再生研究（英文版）》杂志2020年 12 月 12  期发表。

    https://orcid.org/0000-0003-2080-2951(Amadoro Giuseppina)

Abstract: AD, the main cause of dementia in elderly people, is a multifactorial neurodegenerative disorder characterized by a long prodromal phase (starting more than two decades before clinical symptoms appear) with brain accumulation/misfolding of amyloid β (Aβ) in insoluble amyloid plaques and of tau protein in neurofibrillary tangles. Even though the slow-progressing clinical development of the disease opens important diagnostic and therapeutic perspectives for the preventive medicine, there’s a general consensus that the amyloid deposition reaches early a plateau and does not change over time. On the contrary, the tau pathology is tightly linked with synaptic deterioration and neuronal death which eventually lead to the manifestation of classical symptomatology (Jack et al., 2018). Indeed, several lines of evidence support the notion that alterations of tau homeostasis actually drive the neurodegeneration in human tauopathies, including the most common AD where no genetic mutation in microtubule associated protein tau (MAPT) has been reported up to now. To this regard genetic, clinical and histopathological studies have undoutebly shown that abnormalities in tau protein(s) are sufficient to cause, both in vitro and in vivo, synaptic dysfunction, motor/sensorimotor and cognitive deficits indicative of loss of selective vulnerable neuronal populations (Spillantini and Goedert, 2013). Secondly, compelling evidence have also demonstrated that tau proteins have necessary, not-dispensable role in Aβ-dependent neurodegeneration, both in cellular and animal AD models and in elderly individuals (Iqbal and Gong, 2016). Moreover, both the “amyloid-cascade hypothesis” (i.e. Aβ is the initial insult driving tau pathology) and the “dual hit-model” (i.e. tau pathology is independent of Aβ which just provokes the tau spread to neocortex), which have been proposed to explain the etiopathogenesis of AD, posit a crucial place (i.e. induttive and/or permissive) of tau pathobiology in the chains of events ending in synaptic derangement and irreversible loss of neuronal viability (Small and Duff, 2008). Consistently, tau pathology correlates much more strongly than Aβ pathology with neurodegeneration and cognitive impairment, both spatially and temporally. In fact, the amyloid deposition does not cause the pronounced synaptic and neuronal loss which typically characterize the progressive clinical course of AD. Finally, tau is a common downstream effector both in Aβ-dependent and -independent pathogenic mechanisms such as increased amyloid precursor protein (APP) gene dosage/APP-derived-C-Terminal fragment (CTF,C99), cholesterol metabolism/endocytic, trafficking microglial immune activation, apoliprotein E allele epsilon 4.