中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (1): 88-89.doi: 10.4103/1673-5374.175048

• 观点:退行性病与再生 • 上一篇    下一篇

LINGO-1:干预性治疗老年痴呆的新靶点?

  

  • 收稿日期:2015-10-30 出版日期:2016-01-15 发布日期:2016-01-15

Lingo-1: a novel target in therapy for Alzheimer’s disease?

Francesca Fernandez-Enright, Jessica L. Andrews   

  1. Illawarra Health and Medical Research Institute, Centre for Medical and Molecular Bioscience, Faculty of Science, Medicine and Health, University of Wollongong,
    NSW, Australia (Fernandez-Enright F, Andrews JL)
    School of Psychology, Faculty of Social Sciences, University of Wollongong, NSW, Australia (Fernandez-Enright F)
  • Received:2015-10-30 Online:2016-01-15 Published:2016-01-15
  • Contact: Francesca Fernandez-Enright, Ph.D.,fernande@uow.edu.au.

摘要:

阿尔茨海默病(老年痴呆)是一种进行性神经退行性疾病,病理特征为大脑中神经元纤维缠结以及淀粉样蛋白斑的积累。这些淀粉样蛋白斑的生长速率在整个新皮层和海马区有所不同,并在细胞内和细胞外空间从β淀粉样(Aβ)寡聚体中形成。Aβ是淀粉样前体蛋白由β和γ分泌酶蛋白水解的结果。Aβ寡聚体积累会逐渐变得具有毒性并触发神经退变过程开始。文章讨论了在这个过程中Lingo-1或LERN1(富亮氨酸重复神经蛋白1)的作用,Lingo-1是一种跨膜蛋白,在大脑中丰度极高,并与许多神经退行性疾病相关。Lingo-1在阿尔茨海默病病理生理学中发挥关键作用,因为其不仅能够帮助淀粉样前体蛋白β分裂和Aβ片段产生,也可由关键分子信号转导途径引发神经元生长和存活的抑制因素激活。以Lingo-1为靶点的抗体已被改造成能够穿过血脑屏障并在中枢神经系统内抑制LINGO-1。这种LINGO-1拮抗剂目前在进行临床试验II期用于干预性治疗多发性硬化症,并可能被证明是未来阿尔茨海默病治疗方法中极有希望的治疗选择。

Abstract:

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized clinically by gradual cognitive decline including loss of memory, orientation and reasoning, and is pathologically characterized by accumulation of neurofibrillary tangles and amyloid plaques in the brain. The rate of growth of these amyloid plaques differs throughout neocortical and hippocampal regions, and are formed from oligomers of amyloid-β (Aβ) in the intracellular and extracellular space. Aβ is the result of proteolysis of amyloid precursor protein (APP) by β and γ-secretase enzymes. The accumulation of Aβ oligomers becomes progressively toxic and triggers the start of neurodegenerative processes. Here we discuss the role of Lingo-1, or LERN1 (leucine-rich repeat neuronal protein 1) in this process, a transmembrane protein which is highly abundant in the brain and is implicated in numerous neurodegenerative disorders, and demonstrate reasons suggesting its potential for a role in future AD therapy. It appears that Lingo-1 plays a critical role in the AD pathophysiology by both favoring the β-cleavage of APP and the generation of Aβ fragment, but also by the activation of key molecular signaling pathways leading to the inhibition of neuronal outgrowth and survival. An antibody targeting Lingo-1 (BIIB033 produced by Biogen®), has been engineered to be able to cross the blood brain barrier and to antagonize Lingo-1 within the central nervous system. This Lingo-1 antagonist is currently in phase II clinical trials for treating multiple sclerosis and may prove to be a promising treatment option for future AD therapies.