- 最新进展
- 参考文献
引言
Tau蛋白是一种微管相关蛋白，主要存在于神经元中，对维持细胞骨架稳定性和神经元功能至关重要。然而，当Tau蛋白发生异常修饰（如过度磷酸化）时，会形成神经纤维缠结（Neurofibrillary Tangles, NFTs），这是阿尔茨海默病（Alzheimer's Disease, AD）和其他Tau蛋白病的标志性病理特征。近年来，Tau蛋白的研究成为神经退行性疾病领域的热点，不仅因其在疾病机制中的核心作用，还因其作为潜在治疗靶点的重要价值。
Tau蛋白的功能
- Tau蛋白的正常生理功能
维持微管稳定性
Tau蛋白通过结合微管蛋白（α/β-tubulin），促进微管组装并增强其结构稳定性，这对轴突运输（如线粒体、囊泡和营养物质的定向运输）至关重要。
不同剪接亚型（如3R-Tau和4R-Tau）通过微管结合域（MTBD）调控微管动态平衡。
调节神经元形态与可塑性
Tau蛋白参与突触形成和功能维持，影响神经递质释放和突触可塑性（如长时程增强作用，LTP）。
在发育阶段，Tau蛋白表达水平的变化与神经元迁移和轴突生长密切相关。
信号转导与细胞保护
Tau蛋白与激酶（如GSK-3β、CDK5）和磷酸酶（如PP2A）相互作用，参与细胞存活和凋亡信号通路。
近年研究发现，Tau可能通过结合DNA或RNA调控基因表达。
- Tau蛋白的病理功能：从失调到神经退行
当Tau蛋白发生异常翻译后修饰（如过度磷酸化、乙酰化、截断等）时，其生理功能丧失并转化为神经毒性分子，导致以下病理过程：
微管稳定性破坏与轴突运输障碍
过度磷酸化的Tau蛋白从微管上解离，导致微管解体，阻碍轴突运输，引发突触功能障碍和神经元能量衰竭。
神经纤维缠结（NFTs）的形成
错误折叠的Tau蛋白自我聚集，形成不溶性纤维聚集体（如配对螺旋丝PHF和直丝SF），构成NFTs的核心成分。
NFTs在神经元内沉积，最终导致细胞死亡，并释放病理Tau至细胞外，通过“朊病毒样”机制在脑内扩散。
突触毒性与神经炎症
可溶性Tau寡聚体（而非成熟NFTs）可直接损伤突触功能，抑制长时程增强（LTP），影响记忆形成。
NFTs激活小胶质细胞和星形胶质细胞，释放促炎因子（如IL-6、TNF-α），加剧神经退行性病变。
与其他病理蛋白的协同作用
在阿尔茨海默病（AD）中，Tau病理与β-淀粉样蛋白（Aβ）相互作用（“Aβ-Tau假说”）：Aβ可能触发Tau过度磷酸化，而Tau病理则推动疾病进展至晚期。
Tau蛋白作为治疗靶点的研究进展
Tau蛋白病变是多种疾病的共同特征，包括：
- 阿尔茨海默症（NFTs与β-淀粉样斑块共同构成病理核心）。
- 原发性Tau蛋白病：如额颞叶痴呆（FTLD-Tau）、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）。
目前针对Tau蛋白的治疗策略主要集中在以下方向：
- 抑制Tau异常磷酸化：如激酶抑制剂（靶向GSK-3β、CDK5等）。
- 减少Tau聚集：小分子化合物（如亚甲蓝衍生物LMTM）或抗体靶向清除病理性Tau。
- 增强Tau清除：通过激活自噬或泛素-蛋白酶体系统。
- 基因治疗：如反义寡核苷酸（ASOs）降低Tau表达。
- 免疫疗法：抗Tau抗体（如AADvac1、semorinemab）的临床试验正在进行中。
表1.针对Tau病理的临床试验涉及不同的治疗方法
挑战与未来方向
尽管Tau靶向治疗前景广阔，但仍面临诸多挑战：
- 疾病异质性：不同Tau蛋白病的Tau亚型分布不同，需个体化策略。
- 血脑屏障穿透：大分子药物（如抗体）的递送效率问题。
- 生物标志物开发：血液或脑脊液中Tau蛋白（如p-Tau181、p-Tau217）的检测仍需优化。
未来研究需结合多组学技术、类器官模型和人工智能，进一步揭示Tau病理机制，并推动精准医疗的发展。
相关产品推荐：
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Tau重组蛋白产品 |
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表达宿主 : E.coli |
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表达宿主 : E.coli |
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Tau (phospho T217) Recombinant Rabbit mAb (SDT-R205-TT217-4) |
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部分数据分享：
Tau-441/2N4R His Tag Protein, Human （UA030093）
Immobilized Tau-441/2N4R His Tag Protein, Human at 2 μg/mL (100 μL/well) can bind Tau Recombinant Rabbit mAb (SDT-171-67) (Cat. No. S0B0036) with EC50 of 7.3-10.1 ng/mL.
配对推荐：
参考文献：
- Jonathan Gallego-Rudolf; Alex I. Wiesman; Alexa Pichet Binette; Sylvia Villeneuve; Sylvain Baillet.Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.Nature Neuroscience.2024.
- C Bravo; Sarah Naguib; Li Gan. Cellular and pathological functions of tau. Nature Reviews Molecular Cell Biology.2024.
- Novak, P. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat. Aging 1.2021.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/.NCT04445831 .
- Tai, C.-Y. et al. APNmAb005, an anti-tau antibody targeting synaptic tau oligomers, in phase 1 for treatment of Alzheimer’s Disease and primary tauopathies. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04867616 .
- Zhou, J. et al. E2814: an anti-tau therapy engages its CNS target and afects the downstream tangle-specific biomarker MTBR-tau243 in dominantly inherited Alzheimer’s disease. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04619420 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04149860 .2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05466422 .
- Luca, W., Foster, K., McClure, K., Ahlijanian, M. K. & Jefson, M. A phase 1 single-ascendingdose trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous PNT001, a novel mid-domain tau antibody targeting cis-pT231 tau. J. Prev. Alzheimers Dis. 2024.
- Martenyi, F. et al. PRX005, a novel anti-MTBR tau monoclonal antibody: results from a first-in-human double-blind, placebo-controlled, single ascending dose phase 1 study. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03828747.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04759365.
- Permanne, B. et al. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem. Neurosci. 2022.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05195008.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03706885 .
- Verwaerde, P. et al. First-in-human safety, tolerability, and pharmacokinetics of single and multiple doses of AZP2006, a synthetic compound for the treatment of Alzheimer’s disease and related diseases. J. Alzheimers Dis. 2024.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04685590 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03446001.
- Yipeng Wang; Eckhard Mandelkow.Tau in physiology and pathology.Nature Reviews Neuroscience.2015.
优爱蛋白（UA Bio）,重组蛋白专家
优爱蛋白专注于提供药物研发、细胞治疗、基因治疗、基础科研所需各种蛋白类试剂原材料和服务，包括药物靶点蛋白、免疫检查点蛋白、细胞因子、工具酶、 蛋白定制表达、全长跨膜蛋白开发等。优爱致力于为客户提供优质的产品和专业服务，打造具有国际竞争力的高新技术企业。
- Jonathan Gallego-Rudolf; Alex I. Wiesman; Alexa Pichet Binette; Sylvia Villeneuve; Sylvain Baillet.Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults.Nature Neuroscience.2024.
- C Bravo; Sarah Naguib; Li Gan. Cellular and pathological functions of tau. Nature Reviews Molecular Cell Biology.2024.
- Novak, P. et al. ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease. Nat. Aging 1.2021.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/.NCT04445831 .
- Tai, C.-Y. et al. APNmAb005, an anti-tau antibody targeting synaptic tau oligomers, in phase 1 for treatment of Alzheimer’s Disease and primary tauopathies. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04867616 .
- Zhou, J. et al. E2814: an anti-tau therapy engages its CNS target and afects the downstream tangle-specific biomarker MTBR-tau243 in dominantly inherited Alzheimer’s disease. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04619420 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04149860 .2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05466422 .
- Luca, W., Foster, K., McClure, K., Ahlijanian, M. K. & Jefson, M. A phase 1 single-ascendingdose trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of intravenous PNT001, a novel mid-domain tau antibody targeting cis-pT231 tau. J. Prev. Alzheimers Dis. 2024.
- Martenyi, F. et al. PRX005, a novel anti-MTBR tau monoclonal antibody: results from a first-in-human double-blind, placebo-controlled, single ascending dose phase 1 study. Alzheimers Dement. 2023.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03828747.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04759365.
- Permanne, B. et al. O-GlcNAcase inhibitor ASN90 is a multimodal drug candidate for tau and alpha-synuclein proteinopathies. ACS Chem. Neurosci. 2022.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05195008.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03706885 .
- Verwaerde, P. et al. First-in-human safety, tolerability, and pharmacokinetics of single and multiple doses of AZP2006, a synthetic compound for the treatment of Alzheimer’s disease and related diseases. J. Alzheimers Dis. 2024.
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04685590 .
- US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03446001.
- Yipeng Wang; Eckhard Mandelkow.Tau in physiology and pathology.Nature Reviews Neuroscience.2015.
营业执照（三证合一） 