To the Editor,

Tauopathies, including Alzheimer’s disease (AD), are characterized by the accumulation of abnormal tau protein deposits in the brain. Tau exists in multiple heterogenous forms of various polypeptide fragments by enzymatic cleavage and post-translational modifications (PTMs) [1]. Insights from clinical trials of anti-β-amyloid (Aβ) antibodies highlight the importance of epitope selection, as targeting Aβ protofibrils or N-terminus influenced both target engagement and downstream pathogenic processes [2]. Initially, anti-tau antibodies targeting the N-terminus were developed because these N-terminal fragments predominated in AD cerebrospinal fluid (CSF) and were implicated in tau spread [3]. However, these trials ultimately failed [4], aligning with earlier findings that indicated insufficient inhibition of tau seeding [5]. Although other epitopes, such as mid-region, microtubule-binding region (MTBR) and C-terminus, are being explored, the most effective target remains unclear. Certain tau fragments are suggested to play critical roles in tau pathology development [1] and studies in the interstitial fluid (ISF) of tau transgenic mice brains show that secreted tau is primarily truncated during disease progression [6]. The complexity of tau cleavage and PTMs emphasizes the significance of epitope selection, especially in the context of low brain penetration of antibodies, to effectively bind seed-competent forms and counteract propagation.

To investigate this issue, the potency of various anti-tau antibodies under clinical trials was compared using sarkosyl-insoluble fractions isolated from AD patient brains. Inhibition of tau seeding by antibodies targeting the N-terminus (antibody A), mid-region (antibody B), and MTBR (antibody C and D) (Fig. 1a and table S1) was tested using tau fluorescence resonance energy transfer (FRET) cells. Initial study using fraction from a single patient to determine adequate concentration yielded dose-dependent inhibition of tau seeding with anti-tau antibody treatment. Cells treated with anti-acetylated lysine-280 (acK280) antibody, antibody C, showed the most significant decrease in FRET signal at 1 µg/mL (Fig. S1a). Using this concentration as baseline, subsequent tests with insoluble tau fractions from the entorhinal cortex (n = 4) or hippocampus (n = 5) of AD patients revealed that antibody C induced a statistically significant inhibitory effect on tau seeding (Fig. 1b and c, and table S2). With the entorhinal cortex, both antibodies targeting the MTBR, C and D, inhibited tau seeding, with antibody C showing superior effects (Fig. 1b). With the hippocampus, only antibody C was effective (Fig. 1c). Further analysis by Braak stages showed that only antibody C significantly reduced tau seeding in both Braak 3–4 (Fig. S1b) and Braak 5–6 (Fig. S1c). These results indicate that the anti-tau antibody targeting acK280 on MTBR was most potent in inhibiting tau seeding from AD brain extracts.

a A schematic domain map of tau 2N4R isoform and target epitopes of various anti-tau antibodies and epitope peptides. Relative location on the tau isoform of antibodies’ epitope sequences is represented by the antibody’s name and amino acid residue numbers within brackets

b, c FRET signal of human Alzheimer’s disease insoluble tau fraction extract co-incubated with various anti-tau antibodies (1 µg/mL) at endpoint. Tau-FRET cells were treated with entorhinal cortical (n = 4) (b) or hippocampal (n = 5) (c) extract from Alzheimer’s disease patients and various anti-tau antibodies

d ThT signal of acetylated tau aggregates co-incubated with various anti-tau antibodies at endpoint. Acetylated tau aggregates were incubated with ThT fluorescent dyes (1:1 ratio) and anti-tau antibodies at various concentrations for 70 h

e FRET signal of acetylated tau aggregates co-incubated with various anti-tau antibodies at endpoint. Tau-FRET cells were treated with acetylated tau aggregates and anti-tau antibodies at various concentrations

f ThT fluorescence signal of peptides corresponding to target epitope sequences of anti-tau antibodies. Each peptide was incubated with ThT fluorescent dyes (1:1 ratio)

g FRET signal of peptides corresponding to target epitope sequences of anti-tau antibodies. Tau-FRET cells were treated with peptides corresponding to target epitope sequences of anti-tau antibodies at endpoint

Two-way ANOVAs (d, e) and one-way ANOVAs were used for statistical analysis followed by Tukey’s multiple comparisons test. Line graphs present the mean ± SE determined from independent experiments represented by dots, each performed in triplicate. *p < 0.05, **p < 0.01, ***p < 0.001

Full size image

Since tau acetylation is proposed to contribute to accelerated tau aggregation and AD pathology [7] and showed similar FRET signal to AD brain extracts (Fig. 1c), acetylated full-length tau (acTau) was used to illustrate the differing effect of anti-tau antibodies on tau seeding of AD brain extracts, their effect on acTau seeding and aggregation was evaluated with FRET assay and Thioflavin T (ThT) assay. While anti-tau antibodies reduced ThT signal in dose-dependent manner, antibody C showed the greatest inhibition of tau aggregation, reaching near to full removal of amyloid formation, albeit at high concentration of 1000 µg/mL (Fig. 1d). Additionally, tau seeding showed a treatment dose-dependent decrease by anti-tau antibodies. The reduction in tau seeding with antibody C was significantly greater compared to the other antibodies, with increasing treatment concentration (Fig. 1e).

As various sized tau fragments exist in brains and ISF among which few may constitute key tau pathogen [6], we speculated differing effects of antibodies inhibiting tau seeding could be derived from each antibody’s ability to target minimal tau fragments acting as seeding catalyst. We hence generated tau epitope peptides for each anti-tau antibodies targeting near or MTBR itself (Fig. 1a and table S1) to compare the tau aggregation or seeding potency of target epitopes. Aggregation of each epitope peptides was induced with addition of heparin and monitored by ThT assay. Only 275-acK280-286 exhibited an accelerated aggregation curve on ThT assay (Fig. 1f) and FRET intensities were significantly increased in cells treated with 275-acK280-286 (Fig. 1g), suggesting it is the most aggregation-prone and seed-competent species among the epitope peptides tested. Since the target sequence of antibody D, HVPGG, is relatively shorter than other peptides tested, longer tau peptides 295–311 and 358–372 were generated with HVPGG positioned in the middle (Fig. S2a) but these also showed little amyloid formation (Fig. S2b) and seeding (Fig. S2c). Also, as MTBR forms the core of tau aggregates in tauopathies [8] and MTBR fragments were recently detected in patient CSF [9], these fragments might represent the extracellularly released seed-competent tau species, potential targets of therapeutic antibodies (Fig. S2a). We hence investigated whether the MTBR fragments found in tauopathy CSF could aggregate or induce tau seeding. However, MTBR peptides did not induce amyloid formation (Fig. S2d) and seeding (Fig. S2e). These results show that peptide containing acetylated lysine-280 yield highest propensity for aggregation and seeding among the tested tau fragments, suggesting as an appealing target to remove via immunotherapy.

While the antibodies used are not from the exact same batch as those used in clinical trials and may exhibit differences in characteristics such as affinity, the direct comparison of the antigens targeted by the different antibodies (Fig. 1f, g) still supports our conclusion that acK280 is a more efficient target compared to others. MTBR forms a critical component of the β-sheet core of tau tangles [8] and contains the amyloid-forming motifs VQIINK and VQIVYK [10]. Our results also suggest that MTBR antibodies are more effective at inhibiting tau seeding and aggregation than N-terminus antibody, aligning with recent development trends focused on targeting MTBR. The P-G-G-G motif regulates tau aggregation by engaging in β-turn interactions with adjacent VQIINK and VQIVYK motifs, and its perturbation, such as via lysine acetylation, can lead to formation of seed-competent monomers [10]. Lysine deletion or acetylation may neutralize the positive charge within this region, yielding pathogenic neurodegenerative phenotypes [11]. Acetylation of K280, the lysine of VQIINK motif located in the second repeat, plays a key role in tau secretion and propagation. Its inhibition by immunotherapy ameliorated cognitive impairment and tau pathology in tau transgenic mice [12], further validating toxicity of this region. Limitations remain in identifying the exact tau fragments and PTMs that are key pathogens in AD brain ISF. While antibodies targeting the phosphorylated tau, which is also key pathologic tau PTM, are not included in this study [13] as well as preclinical antibodies targeting other acetylation sites [14], this study suggests that targeting acK280 in the MTBR region presents a promising approach among the latest clinical trial-stage antibodies tested. Future studies could explore comparative efficacies using additional antibodies, possibly in the context of targeting diverse PTM profile of tau pathologies [1].

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

PTMs:

Post-translational modifications

Aβ:

Amyloid beta

CSF:

Cerebrospinal fluid

MTBR:

Microtubule-binding region

ISF:

Interstitial fluid

FRET:

Fluorescence resonance energy transfer

AcTau:

Acetylated full-length tau

ThT:

Thioflavin T

1. Yang J, Shen N, Shen J, Yang Y, Li HL. Complicated role of post-translational modification and protease-cleaved fragments of tau in Alzheimer’s Disease and other tauopathies. Mol Neurobiol. 2024;61(7):4712–31.

   Article CAS PubMed Google Scholar

2. Söderberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, et al. Lecanemab, Aducanumab, and Gantenerumab - binding profiles to different forms of amyloid-Beta might explain Efficacy and Side effects in clinical trials for Alzheimer’s Disease. Neurotherapeutics: J Am Soc Experimental Neurother. 2023;20(1):195–206.

   Article Google Scholar

3. Bespalov A, Courade JP, Khiroug L, Terstappen GC, Wang Y. A call for better understanding of target engagement in Tau antibody development. Drug Discov Today. 2022;27(11):103338.

   Article CAS PubMed Google Scholar

4. Imbimbo BP, Balducci C, Ippati S, Watling M. Initial failures of anti-tau antibodies in Alzheimer’s disease are reminiscent of the amyloid-β story. Neural Regeneration Res. 2023;18(1):117–8.

   Article Google Scholar

5. Courade JP, Angers R, Mairet-Coello G, Pacico N, Tyson K, Lightwood D, et al. Epitope determines efficacy of therapeutic anti-tau antibodies in a functional assay with human Alzheimer tau. Acta Neuropathol. 2018;136(5):729–45.

   Article CAS PubMed PubMed Central Google Scholar

6. Barini E, Plotzky G, Mordashova Y, Hoppe J, Rodriguez-Correa E, Julier S, et al. Tau in the brain interstitial fluid is fragmented and seeding-competent. Neurobiol Aging. 2022;109:64–77.

   Article CAS PubMed Google Scholar

7. Cohen TJ, Guo JL, Hurtado DE, Kwong LK, Mills IP, Trojanowski JQ, et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun. 2011;2:252.

   Article PubMed Google Scholar

8. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature. 2017;547(7662):185–90.

   Article CAS PubMed PubMed Central Google Scholar

9. Horie K, Barthélemy NR, Spina S, VandeVrede L, He Y, Paterson RW, et al. CSF tau microtubule-binding region identifies pathological changes in primary tauopathies. Nat Med. 2022;28(12):2547–54.

   Article CAS PubMed PubMed Central Google Scholar

10. Li L, Nguyen BA, Mullapudi V, Li Y, Saelices L, Joachimiak LA. Disease-associated patterns of acetylation stabilize tau fibril formation. Structure (London, England: 1993). 2023.

11. Trzeciakiewicz H, Tseng JH, Wander CM, Madden V, Tripathy A, Yuan CX, et al. A dual pathogenic mechanism links tau acetylation to sporadic Tauopathy. Sci Rep. 2017;7:44102.

    Article CAS PubMed PubMed Central Google Scholar

12. Song HL, Kim NY, Park J, Kim MI, Jeon YN, Lee SJ et al. Monoclonal antibody Y01 prevents tauopathy progression induced by lysine 280-acetylated tau in cell and mouse models. J Clin Investig. 2023;133(8).

13. Xia Y, Prokop S, Giasson BI. Don’t Phos over tau: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegener. 2021;16(1):37.

    Article CAS PubMed PubMed Central Google Scholar

14. Parra Bravo C, Krukowski K, Barker S, Wang C, Li Y, Fan L, et al. Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury. Mol Neurodegeneration. 2024;19(1):1–19.

    Article Google Scholar

Download references

We thank the Antibody Development Core Laboratory at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Medical Center for producing the recombinant monoclonal antibody protein.

We thank the Human Brain Bank of Seoul National University (SNUHBB) and Korea Brain Bank Network (KBBN-00-DD01-18004) for supplying the human brain material and thank the brain tissue donors and their relatives for enabling the neuropathological studies described in this paper.

Oscotec Inc. contributed to the co-development of ADEL-Y01 and participated in the review of this manuscript.

This work was supported by the National Research Foundation of Korea (NRF) MRC grant funded by the Korean government (MSIT) (2018R1A5A2020732) and a grant of the Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (grant number: HU23C0296).

1. Ha-Lim Song and Min-Seok Kim contributed equally to this work.

Authors and Affiliations

1. ADEL Institute of Science & Technology (AIST), ADEL, Inc, Seoul, Korea

   Ha-Lim Song, Min-Seok Kim & Seung-Yong Yoon

2. Department of Brain Science, Asan Medical Center, University of Ulsan College of Medicine, Brain Korea 21 project, Seoul, Korea

   Woo-Young Cho, Ye-Seul Yoo, Jae-You Kim, Tae-Wook Kim, Dong-Hou Kim & Seung-Yong Yoon

3. Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea

   Hyori Kim

4. Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, Korea

   Seung-Yong Yoon

1. Ha-Lim SongView author publications

   You can also search for this author in PubMed Google Scholar

2. Min-Seok KimView author publications

   You can also search for this author in PubMed Google Scholar

3. Woo-Young ChoView author publications

   You can also search for this author in PubMed Google Scholar

4. Ye-Seul YooView author publications

   You can also search for this author in PubMed Google Scholar

5. Jae-You KimView author publications

   You can also search for this author in PubMed Google Scholar

6. Tae-Wook KimView author publications

   You can also search for this author in PubMed Google Scholar

7. Hyori KimView author publications

   You can also search for this author in PubMed Google Scholar

8. Dong-Hou KimView author publications

   You can also search for this author in PubMed Google Scholar

9. Seung-Yong YoonView author publications

   You can also search for this author in PubMed Google Scholar

Contributions

H.L.S., M.S.K., D.H.K., and S.Y.Y. contributed to the conception and design of the study. H.L.S., M.S.K., and S.Y.Y. contributed to the acquisition and analysis of data. All authors contributed to drafting the text or preparing the figures.

Corresponding author

Correspondence to Seung-Yong Yoon.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

S.Y.Y. founded ADEL, Inc; S.Y.Y., D.H.K., H.L.S., and M.S.K. have stocks or stock options in ADEL, Inc., which owns patent rights to antibody C that was used in this study.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Below is the link to the electronic supplementary material.

Supplementary Material 1

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

Cite this article

Song, HL., Kim, MS., Cho, WY. et al. Comparing anti-tau antibodies under clinical trials and their epitopes on tau pathologies. Mol Neurodegeneration 19, 76 (2024). https://doi.org/10.1186/s13024-024-00769-x

Download citation

• Received: 16 August 2024

• Accepted: 11 October 2024

• Published: 19 October 2024

• DOI: https://doi.org/10.1186/s13024-024-00769-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

 致编辑：

包括阿尔茨海默病 （AD） 在内的 tau 蛋白病的特征是异常的 tau 蛋白沉积物在大脑中积累。Tau 通过酶促切割和翻译后修饰 （PTM） 以多种异质形式存在于各种多肽片段中 [1]。抗 β-淀粉样蛋白 （Aβ） 抗体临床试验的见解强调了表位选择的重要性，因为靶向 Aβ 原纤维或 N 末端会影响靶标参与和下游致病过程 [2]。最初，靶向 N 端的抗 tau 抗体被开发出来，因为这些 N 端片段在 AD 脑脊液 （CSF） 中占主导地位，并且与 tau 扩散有关[3]。然而，这些试验最终失败了 [4]，这与早期的发现一致，即表明对 tau 播种的抑制不足 [5]。尽管正在探索其他表位，例如中区、微管结合区 （MTBR） 和 C 端，但最有效的靶点仍不清楚。某些 tau 片段被认为在 tau 病理发展中起关键作用 [1]，对 tau 转基因小鼠大脑间质液 （ISF） 的研究表明，分泌的 tau 在疾病进展过程中主要被截短 [6]。tau 切割和 PTM 的复杂性强调了表位选择的重要性，尤其是在抗体脑渗透率低的情况下，可以有效结合种子感受态形式并抵消繁殖。

为了研究这个问题，使用从 AD 患者大脑中分离的 sarkosyl 不溶性组分比较了临床试验中各种抗 tau 抗体的效力。使用 tau 荧光共振能量转移 （FRET） 细胞测试了靶向 N 端（抗体 A）、中间区（抗体 B）和 MTBR（抗体 C 和 D）的抗体对 tau 接种的抑制作用（图 1a 和表 S1）。使用来自单个患者的分数来确定足够浓度的初步研究产生了抗 tau 抗体治疗对 tau 接种的剂量依赖性抑制。用抗乙酰化赖氨酸-280 （acK280） 抗体 C 处理的细胞在 1 μg/mL 时显示 FRET 信号最显着降低（图 S1a）。以该浓度为基线，随后对来自 AD 患者的内嗅皮层 （n = 4） 或海马体 （n = 5） 的不溶性 tau 组分进行的测试表明，抗体 C 对 tau 接种具有统计学意义的抑制作用（图 1b 和 c，以及表 S2）。对于内嗅皮层，靶向 MTBR C 和 D 的两种抗体都抑制了 tau 接种，而抗体 C 显示出优异的效果（图 1b）。对于海马体，只有抗体 C 有效（图 1c）。Braak 分期的进一步分析表明，在 Braak 3-4（图 S1b）和 Braak 5-6（图 S1c）中，只有抗体 C 显著减少了 tau 接种。这些结果表明，靶向 MTBR 上 acK280 的抗 tau 抗体在抑制 AD 脑提取物的 tau 接种方面最有效。

a tau 2N4R 亚型和各种抗 tau 抗体和表位肽的靶表位的示意图结构域图。抗体表位序列在 tau 亚型上的相对位置由括号内的抗体名称和氨基酸残基编号表示

b、c 人阿尔茨海默病不溶性 tau 组分提取物与各种抗 tau 抗体 （1 μg/mL） 共孵育终点的 FRET 信号。用阿尔茨海默病患者的内嗅皮质 （n = 4） （b） 或海马 （n = 5） （c） 提取物和各种抗 tau 抗体处理 Tau-FRET 细胞

d 在终点与各种抗 tau 抗体共孵育的乙酰化 tau 聚集体的 ThT 信号。乙酰化 tau 聚集体与不同浓度的 ThT 荧光染料 （1：1 比例） 和抗 tau 抗体一起孵育 70 小时

在终点与各种抗 tau 抗体共孵育的乙酰化 tau 聚集体的 e FRET 信号。用不同浓度的乙酰化 tau 聚集体和抗 tau 抗体处理 tau-FRET 细胞

f 对应于抗 tau 抗体的靶表位序列的肽的 ThT 荧光信号。将每种肽与 ThT 荧光染料（比例为 1：1）一起孵育

与抗 tau 抗体的靶表位序列相对应的肽的 g FRET 信号。在终点处用与抗 tau 抗体的靶表位序列相对应的肽处理 Tau-FRET 细胞

使用双向方差分析 （d、e） 和单向方差分析进行统计分析，然后进行 Tukey 多重比较检验。折线图显示了由点表示的独立实验确定的 ± SE 平均值，每个实验一式三份。*p < 0.05， **p < 0.01， ***p < 0.001

 全尺寸图像

由于 tau 乙酰化被认为有助于加速 tau 聚集和 AD 病理学 [7]，并且显示出与 AD 脑提取物相似的 FRET 信号（图 1c），乙酰化全长 tau （acTau） 用于说明抗 tau 抗体对 AD 脑提取物 tau 接种的不同影响，它们对 acTau 接种和聚集的影响通过 FRET 测定和硫黄素 T （ThT） 测定进行评估。虽然抗 tau 抗体以剂量依赖性方式降低 ThT 信号，但抗体 C 对 tau 聚集的抑制作用最大，几乎完全去除淀粉样蛋白形成，尽管浓度高达 1000 μg/mL（图 1d）。此外，tau 接种显示抗 tau 抗体的治疗剂量依赖性降低。随着处理浓度的增加，与其他抗体相比，抗体 C 对 tau 接种的减少显著更大（图 1e）。

由于大脑和 ISF 中存在各种大小的 tau 片段，其中少数可能构成关键的 tau 病原体 [6]，我们推测抑制 tau 播种的抗体的不同作用可能来自每种抗体靶向作为播种催化剂的最小 tau 片段的能力。因此，我们为靶向 Near 或 MTBR 本身的每种抗 tau 抗体生成了 tau 表位肽（图 1a 和表 S1），以比较靶表位的 tau 聚集或接种效力。添加肝素诱导每个表位肽的聚集，并通过 ThT 测定进行监测。只有 275-acK280-286 在 ThT 测定中表现出加速的聚集曲线（图 1f），并且在用 275-acK280-286 处理的细胞中 FRET 强度显着增加（图 1g），表明它是测试表位肽中最容易聚集和具有种子能力的物种。由于抗体 D 的靶序列 HVPGG 相对短于其他测试的肽，因此 HVPGG 位于中间（图 S2a）会产生较长的 tau 肽 295-311 和 358-372，但它们也显示出很少的淀粉样蛋白形成（图 S2b）和接种（图 S2c）。此外，由于 MTBR 在 tau 蛋白病中形成 tau 聚集体的核心 [8]，并且最近在患者 CSF 中检测到 MTBR 片段 [9]，这些片段可能代表细胞外释放的具有种子能力的 tau 物种，这是治疗性抗体的潜在靶标（图 S2a）。因此，我们研究了在 tau 病 CSF 中发现的 MTBR 片段是否可以聚集或诱导 tau 播种。然而，MTBR 肽不诱导淀粉样蛋白形成（图 S2d）和接种（图 S2e）。 这些结果表明，含有乙酰化赖氨酸-280 的肽在测试的 tau 片段中产生最高的聚集和接种倾向，表明通过免疫疗法去除是一个有吸引力的靶标。

虽然使用的抗体与临床试验中使用的抗体不完全相同，并且可能在亲和力等特性上表现出差异，但不同抗体靶向抗原的直接比较（图 1f、g）仍然支持我们的结论，即 acK280 与其他靶标相比是更有效的靶标。MTBR 形成 tau 缠结 β 片核心的关键组分 [8]，并包含淀粉样蛋白形成基序 VQIINK 和 VQIVYK [10]。我们的结果还表明，MTBR 抗体在抑制 tau 种子和聚集方面比 N 端抗体更有效，这与最近专注于靶向 MTBR 的发展趋势一致。P-G-G-G 基序通过与相邻的 VQIINK 和 VQIVYK 基序进行β转相互作用来调节 tau 聚集，其扰动（例如通过赖氨酸乙酰化）可导致种子感受态单体的形成 [10]。赖氨酸缺失或乙酰化可能会中和该区域内的正电荷，产生致病性神经退行性表型 [11]。K280 的乙酰化是位于第二个重复序列的 VQIINK 基序的赖氨酸，在 tau 蛋白的分泌和传播中起关键作用。免疫疗法对它的抑制改善了 tau 转基因小鼠的认知障碍和 tau 病理 [12]，进一步验证了该区域的毒性。在识别作为 AD 脑 ISF 关键病原体的确切 tau 片段和 PTM 方面仍然存在局限性。虽然本研究未包括靶向磷酸化 tau（也是关键病理性 tau PTM）的抗体 [13]，也没有包括靶向其他乙酰化位点的临床前抗体 [14]，但该研究表明，在 MTBR 区域靶向 acK280 在测试的最新临床试验阶段抗体中提供了一种有前途的方法。 未来的研究可以探索使用其他抗体的比较疗效，可能是在靶向 tau 病理的不同 PTM 谱的背景下 [1]。

当前研究期间使用和/或分析的数据集可应合理要求从通讯作者处获得。

 PTM：

翻译后修饰

 甲醇 β：

 β 淀粉样蛋白

 脑脊液：

 脑脊液

 MTBR：

微管结合区

 ISF：

 间质液

 品：

荧光共振能量转移

 AcTau：

乙酰化全长 tau

 总谐波：

 硫黄素 T

1. 
   杨 J， 沈 N， 沈 J， 杨 Y， 李 HL.翻译后修饰和 tau 蛋白酶裂解片段在阿尔茨海默病和其他 tau 蛋白病中的复杂作用。分子神经生物学。2024;61(7):4712–31.

   
   论文 CAS PubMed Google Scholar

2. 
   Söderberg L， Johannesson M， Nygren P， Laudon H， Eriksson F， Osswald G， et al. Lecanemab， Aducanumab， and Gantenerumab - 与不同形式的淀粉样蛋白-β 的结合谱可能解释了阿尔茨海默病临床试验中的疗效和副作用。神经治疗学：J Am Soc 实验神经。2023;20(1):195–206.

    文章 Google Scholar

3. 
   Bespalov A， Courade JP， Khiroug L， Terstappen GC， Wang Y.呼吁更好地了解 Tau 抗体开发中的靶标参与。今日毒品迪斯科夫。2022;27(11):103338.

   
   论文 CAS PubMed Google Scholar

4. 
   Imbimbo BP， Balducci C， Ippati S， Watling M. 阿尔茨海默病中抗 tau 抗体的最初失败让人想起淀粉样蛋白β的故事。神经再生研究 2023;18(1):117–8.

    文章 Google Scholar

5. 
   Courade JP、Angers R、Mairet-Coello G、Pacico N、Tyson K、Lightwood D 等人。表位确定治疗性抗 tau 抗体在人阿尔茨海默病 tau 功能测定中的疗效。神经病理学报。2018;136(5):729–45.

   
   论文： CAS PubMed， PubMed， Central Google Scholar

6. 
   Barini E、Plotzky G、Mordashova Y、Hoppe J、Rodriguez-Correa E、Julier S 等人。脑间质液中的 Tau 是碎片化的，并且具有播种能力。神经生物学衰老。2022;109:64–77.

   
   论文 CAS PubMed Google Scholar

7. 
   Cohen TJ、Guo JL、Hurtado DE、Kwong LK、Mills IP、Trojanowski JQ 等人。tau 的乙酰化抑制其功能并促进病理性 tau 聚集。Nat Commun.2011;2:252.

   
   文章 PubMed 谷歌学术

8. 
   Fitzpatrick AWP、Falcon B、He S、Murzin AG、Murshudov G、Garringer HJ 等人。阿尔茨海默病 tau 丝的冷冻电镜结构。自然界。2017;547(7662):185–90.

   
   论文： CAS PubMed， PubMed， Central Google Scholar

9. 
   Horie K， Barthélemy NR， Spina S， VandeVrede L， He Y， Paterson RW， et al. CSF tau 微管结合区可识别原发性 tau 蛋白病的病理变化。国家医学 2022;28(12):2547–54.

   
   论文： CAS PubMed， PubMed， Central Google Scholar

10. 
    李 L， 阮 BA， Mullapudi V， 李 Y， Saelices L， Joachimiak LA。疾病相关的乙酰化模式稳定了 tau 原纤维的形成。结构（英国伦敦：1993 年）。2023.

11. 
    Trzeciakiewicz H、Tseng JH、Wander CM、Madden V、Tripathy A、Yuan CX 等人。双重致病机制将 tau 乙酰化与散发性 tau 蛋白病联系起来。科学代表 2017;7：44102。

    
    论文： CAS PubMed， PubMed， Central Google Scholar

12. 
    Song HL、Kim NY、Park J、Kim MI、Jeon YN、Lee SJ 等人。单克隆抗体 Y01 可防止细胞和小鼠模型中赖氨酸 280-乙酰化 tau 诱导的 tau 蛋白病进展。J Clin 调查。2023;133(8).

13. 
    夏 Y， Prokop S， Giasson BI.不要在 tau 上磷：阿尔茨海默病和其他 tau 蛋白病中针对 tau 磷酸化的临床生物标志物和疗法的最新进展。Mol 神经退化者。2021;16(1):37.

    
    论文： CAS PubMed， PubMed， Central Google Scholar

14. 
    Parra Bravo C、Krukowski K、Barker S、Wang C、Li Y、Fan L 等人。抗乙酰化 tau 免疫疗法对 tau 蛋白病和脑损伤具有神经保护作用。Mol 神经退行性变。2024;19(1):1–19.

     文章 Google Scholar

 下载参考资料

我们感谢峨山医学中心 ConveRgence mEDIcine 研究中心 （CREDIT） 的抗体开发核心实验室生产重组单克隆抗体蛋白。

我们感谢首尔国立大学人脑库 （SNUHBB） 和韩国脑库网络 （KBBN-00-DD01-18004） 提供人脑材料，并感谢脑组织捐献者及其亲属促成本文中描述的神经病理学研究。

Oscotec Inc. 为 ADEL-Y01 的共同开发做出了贡献，并参与了该手稿的审查。

这项工作得到了韩国政府 （MSIT） 资助的韩国国家研究基金会 （NRF） MRC 赠款 （2018R1A5A2020732） 和韩国痴呆症研究项目的赠款，通过韩国痴呆症研究中心 （KDRC） 资助，由韩国卫生与福利部和科学与信息通信技术部资助（资助号：HU23C0296）。

1. 
   Ha-Lim Song 和 Min-Seok Kim 对这项工作做出了同等贡献。

 作者和单位

1. 
   ADEL科学与技术研究所（AIST），ADEL， Inc，首尔，韩国

   
   Ha-Lim Song， Min-Seok Kim & Seung-Yong Yoon

2. 
   蔚山大学医学院峨山医学中心脑科学系，Brain Korea 21 项目，韩国首尔

   
   Woo-Young Cho， Ye-Seul Yoo， Jae-You Kim， Tae-Wook Kim， Dong-Hou Kim & Seung-Yong Yoon

3. 
   韩国首尔峨山医学中心峨山生命科学研究所融合医学研究中心

    金孝利

4. 
   韩国首尔蔚山大学医学院干细胞免疫调节研究中心 （SCIRC）

   Seung-Yong Yoon

1. 
   宋夏林查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

2. 
   金珉锡查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

3. 
   赵宇英 Woo-Young Cho查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

4. 
   柳艺瑟查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

5. 
   Jae-You Kim 金查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

6. 
   金泰旭查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

7. 
   金孝利查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

8. 
   金东侯 Dong-Hou Kim查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

9. 
   Seung-Yong Yoon 尹承勇查看作者出版物

   
   您也可以在 PubMed Google Scholar 中搜索此作者

 贡献

H.L.S.、M.S.K.、D.H.K. 和 S.Y.Y. 为这项研究的构思和设计做出了贡献。H.L.S.、M.S.K. 和 S.Y.Y. 为数据的获取和分析做出了贡献。所有作者都为起草文本或准备图表做出了贡献。

 通讯作者

与 Seung-Yong Yoon 的通信。

道德批准和参与同意

 不適用。

 同意发布

 不適用。

 利益争夺

S.Y.Y. 创立了 ADEL， Inc;S.Y.Y.、D.H.K.、H.L.S. 和 M.S.K. 拥有 ADEL， Inc. 的股票或股票期权，该公司拥有本研究中使用的抗体 C 的专利权。

 出版商注

施普林格·自然 （Springer Nature） 对已发布的地图和机构隶属关系中的管辖权主张保持中立。

以下是电子补充材料的链接。

 补充材料 1

开放获取本文根据 Creative Commons Attribution 4.0 International License 获得许可，该许可允许以任何媒体或格式使用、共享、改编、分发和复制，前提是您对原作者和来源给予适当的信任，提供指向 Creative Commons 许可的链接，并说明是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的致谢行中另有说明。如果材料未包含在文章的 Creative Commons 许可中，并且您的预期用途未被法律法规允许或超出允许的用途，您将需要直接从版权所有者处获得许可。要查看此许可证的副本，请访问 http://creativecommons.org/licenses/by/4.0/。知识共享公共领域专用弃权 （http://creativecommons.org/publicdomain/zero/1.0/） 适用于本文中提供的数据，除非在数据的鸣谢行中另有说明。

 重印本和权限

 引用本文

 下载引文

• 
  收稿日期： 2024-08-16

• 
  录用日期： 2024-10-11

• 
  出版日期：2024 年 10 月 19 日

 使用本文

您与之共享以下链接的任何人都可以阅读此内容：

抱歉，本文目前没有可共享链接。

由 Springer Nature SharedIt 内容共享计划提供