Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies.
Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies.
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DOI：
10.1126/science.abb8255
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发表时间：
2021-02-26
期刊：
影响因子：
--
通讯作者：
Mucke L
中科院分区：
文献类型：
--
作者：
Chang CW;Shao E;Mucke L
一些证据表明tau蛋白与多种脑部疾病的发病机制有关，包括阿尔茨海默病、其他神经退行性疾病、自闭症和癫痫。Tau蛋白在神经元中含量丰富，并与微管相互作用，但其在大脑中的主要功能仍有待确定。这些功能可能涉及与多种生物过程相关的信号通路的调节。信息性疾病模型已经揭示了过多的异常tau物种和可能导致神经元功能障碍和丧失的机制，但它们各自贡献的相对重要性尚不确定。这种知识差距对开发真正有效的治疗策略构成了重大障碍。目前扩大和加强将机制见解转化为tau相关疗法的努力应该解决这个问题，并可以为许多破坏性疾病提供更好的治疗方法。图：潜在的tau病理机制。开发有效的tau靶向治疗方法将需要更好地了解tau究竟如何导致阿尔茨海默病和其他中枢神经系统疾病。潜在的机制可能分为三大类。然而，在真正与疾病相关的情况下，个体机制的相对致病影响和总体重要性尚未确定，并且在疾病甚至患者之间可能有所不同。右边的蓝色方框表示tau蛋白活动不直接介导，而是间接促进或促进致病过程。扩大开发tau靶向疗法的努力将揭示这种神秘的蛋白质，并可能为多种脑部疾病提供更好的治疗方法。微管相关蛋白tau与阿尔茨海默病和一系列其他神经退行性疾病（称为“tau病”）的发病机制有关。随着世界各地老龄化人口中tau病患者的数量不断增加，对这种蛋白质的基础生物学和tau靶向治疗的发展的兴趣正在迅速扩大。最近对这种内在无序蛋白质复杂性的研究表明，tau是一个有价值但具有挑战性的靶标，其多面性可能需要多管齐下的治疗方法。通过选择性剪接从单个基因衍生而来的tau蛋白，已经在人脑中鉴定出了六种主要的同工型。此外，tau蛋白受到许多不同的翻译后修饰，进一步表明它可能受到多个过程的调控，并可能参与多种功能。人们普遍认为Tau蛋白能够稳定微管。然而，体内tau蛋白的实验性减少或消融并不会改变许多可能依赖于微管的神经特性和过程，包括神经元完整性、轴突运输、突触形成和复杂的脑功能。虽然tau蛋白的减少似乎对未经操作的大脑影响很小，但它可以预防或减少异常的细胞信号、神经网络功能障碍（例如癫痫活动）和由多种疾病过程引起的行为改变，这表明其他致病因素需要tau蛋白的活动来引起这些紊乱。除了这种“启用旁观者”的作用外，tau与大量其他蛋白质的相互作用可能导致功能的不利增益，这与异常tau结构和组装的形成有关，也可能由其引起。由于异常形式的tau触发了过多的病理机制，针对单个下游机制的治疗效果可能有限，除非特定机制的相对致病重要性已在实验模型中得到很好的确立，从而允许对因果关系进行结论性验证。虽然很多注意力都集中在tau病变中tau的异常聚集和tau“种子”在神经元间传播的能力上，但繁殖tau的内化似乎并不会损害神经元的存活或大脑功能。此外，在没有异常tau内含物的疾病模型中，tau减少也可以预防或减少神经网络功能障碍和行为异常，这表明tau不仅仅是聚集和传播。一种有希望的tau靶向治疗策略的多样化正在开始解决这一复杂性。降低整体tau水平可能具有最大的潜力，因为这种策略绕过了在任何给定条件下哪种形式的tau和哪种下游机制最有害的未解决问题。许多开发更好的神经退行性疾病治疗方法的努力都失败了，这在很大程度上是因为对疾病机制的理解不足，也许是因为太多的基础知识差距、对数据的替代解释和方法复杂性没有得到应有的重视。这篇综述强调了对tau的理解中的重要空白，以及填补这些空白所需的方法学进展。它还指出了可能使tau相关科学发现转化为更好的治疗方法复杂化的障碍，并提供了克服这些挑战的实用策略。尽管迄今为止已经取得了非凡的进展，但tau在成人和衰老的大脑中发挥的主要生理功能仍有待确定。另一个关键目标是开发更好的实验模型和技术来严格比较不同的tau物种和病理机制，特别是它们对神经元功能和体内存活的相对影响。为了开发真正有用的生物标志物和有效的治疗方法，严格区分关联和因果关系将是至关重要的。在确定阿尔茨海默病和其他tau具有因果或促成作用的疾病中神经元功能障碍和死亡的主要驱动因素之前，似乎应该谨慎地关注实用策略，例如整体tau减少，同时也要扩大努力进一步验证更具体目标和方法的重要性。降低整体tau水平的研究方法包括靶向tau的反义寡核苷酸，该方法已进入早期阿尔茨海默病的临床试验，以及可以调节tau产生或降解的小分子药物的开发。最理想的tau靶向治疗方法将对各种tau病变有效，并且价格合理，易于获得，并且在长期给予可能服用多种其他药物的脆弱人群时具有良好的耐受性。
Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer’s disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions. Summary Figure: Potential tau pathomechanisms. Developing effective tau-targeting therapeutics will require a better understanding of how exactly tau contributes to Alzheimer’s disease and other disorders of the central nervous system. Potential mechanisms likely fall into the three broad categories shown. However, the relative pathogenic impact and overall importance of individual mechanisms have yet to be defined in truly disease-relevant contexts and may differ among diseases and even patients. The blue box on the right indicates tau activities that do not directly mediate but indirectly promote or facilitate pathogenic processes. Expanding efforts to develop tau-targeting therapeutics will shed light on this enigmatic protein and could yield better treatments for multiple brain disorders. The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer’s disease and a range of other neurodegenerative disorders (called “tauopathies”). As the number of people with tauopathies is rising in aging populations across the world, interest in the fundamental biology of this protein and in the development of tau-targeting treatments have been expanding rapidly. Recent insights into the complexity of this intrinsically disordered protein suggest that tau is a worthy but challenging target whose multifaceted nature will likely require a multipronged therapeutic approach. Derived from a single gene by alternative splicing, six major isoforms of tau have been identified in the human brain. In addition, tau is subject to many different posttranslational modifications, further indicating that it may be regulated by multiple processes and may participate in diverse functions. Tau is widely presumed to stabilize microtubules. However, the experimental reduction or ablation of tau in vivo does not alter many neural properties and processes that likely depend on microtubules, including neuronal integrity, axonal transport, synapse formation, and complex brain functions. Although tau reduction seems to have minimal effects on otherwise unmanipulated brains, it can prevent or diminish aberrant cell signaling, neural network dysfunctions (e.g., epileptic activity) and behavioral alterations caused by diverse disease processes, which suggests that tau activities are needed for other pathogenic triggers to cause these derangements. In addition to this “enabling bystander” role, tau’s interactions with a large number of other proteins can cause adverse gains of function, which are associated with—and possibly caused by— the formation of abnormal tau structures and assemblies. Because abnormal forms of tau trigger a plethora of pathomechanisms, targeting individual downstream mechanisms may have limited therapeutic impact, unless the relative pathogenic importance of the specific mechanism has been well established in experimental models that allow for conclusive validation of cause-and-effect relationships. Although much attention has focused on the abnormal aggregation of tau in tauopathies and on the ability of tau “seeds” to spread from neuron to neuron, internalization of propagating tau does not appear to impair neuronal survival or brain functions. Moreover, tau reduction prevents or diminishes neural network dysfunction and behavioral abnormalities also in disease models that do not have abnormal tau inclusions, which suggests that there is more to tau than aggregation and propagation. A promising diversification of tau-targeting therapeutic strategies is beginning to address this complexity. Lowering overall tau levels may have the greatest potential, as this strategy bypasses the unresolved questions of which forms of tau and which downstream mechanisms are most detrimental in any given condition. Many efforts to develop better treatments for neurodegenerative diseases have failed, in large part because of an inadequate understanding of disease mechanisms and, perhaps, because too many fundamental knowledge gaps, alternative interpretations of data, and methodological complexities did not receive the attention they deserved. This Review highlights important gaps in the understanding of tau and the methodological advances needed to fill them. It also pinpoints obstacles that could complicate the translation of tau-related scientific discoveries into better therapeutics and offers pragmatic strategies to overcome these challenges. Despite the extraordinary progress that has been made to date, the main physiological functions that tau fulfills in the adult and aging brain remain to be defined. Another critical objective is to develop better experimental models and technologies to rigorously compare different tau species and pathomechanisms, particularly their relative impacts on neuronal functions and survival in vivo. For the development of truly informative biomarkers and effective therapeutics, it will be critical to rigorously differentiate between associations and cause-and-effect relationships. Until the main drivers of neuronal dysfunction and demise have been identified for Alzheimer’s disease and other conditions in which tau has a causal or enabling role, it seems prudent to focus on pragmatic strategies, such as overall tau reduction, while also expanding efforts to further validate the importance of more specific targets and approaches. Investigational approaches to lower overall tau levels include tau-targeting antisense oligonucleotides, which have advanced into a clinical trial for early Alzheimer’s disease, and the development of small-molecule drugs that can modulate the production or degradation of tau. The most desirable tau-targeting therapeutics would be efficacious across diverse tauopathies, as well as affordable, easy to access, and well tolerated when administered over long periods of time to fragile groups of people who likely take multiple other medications.
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影响因子：
15.1
作者：
Caillet-Boudin ML;Buée L;Sergeant N;Lefebvre B
通讯作者：
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影响因子：
16.6
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15
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作者：
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通讯作者：
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