Hensley Kenneth, Kursula Petri
Department of Pathology, University of Toledo Health Science Campus, Toledo, OH, USA.
Department of Biomedicine, University of Bergen, Bergen, Norway.
J Alzheimers Dis. 2016 Apr 15;53(1):1-14. doi: 10.3233/JAD-160076.
Alzheimer's disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.
长期以来，阿尔茨海默病（AD）一直被视为一种必然由异常的淀粉样β蛋白前体（AβPP）加工、功能失调的tau蛋白加工或这两种因素共同作用所导致的病理状态。这是一个合理的假设，因为淀粉样β肽（Aβ）积累和tau蛋白过度磷酸化是AD的典型组织学特征，而且因为AβPP和tau基因突变可在人类中引发AD或在动物模型中导致类似AD的特征。尽管如此，其他蛋白质参与者正在出现，有人认为它们是AD亚组中的重要病因参与者，并且可能是新的可药物作用靶点。特别是，微管相关蛋白CRMP2（塌陷反应介导蛋白2）与tau蛋白有显著相似之处，并且同样与AD相关。与tau蛋白一样，CRMP2动态调节微管稳定性；它受相同激酶作用；在神经原纤维缠结（NFTs）中类似地聚集；并且当被隔离在NFTs中时，与关键的突触稳定因子形成复合物。此外，CRMP2正被公认为一种重要的衔接蛋白，参与囊泡运输、淀粉样蛋白生成和自噬，而tau蛋白则不然。本综述在AD的背景下系统地比较了CRMP2和tau蛋白的生物学特性，并探讨了CRMP2是AD中具有病因学意义的蛋白且参与可合理用于治疗获益的途径这一假说。
