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Tau 蛋白-阿尔茨海默症(AD)治疗新天地

AD(Alzhemier Disease) 是德国医生阿尔茨海默最先发现的一种脑神经疾病。它的主要症状有两个:一是 β-淀粉样蛋白在神经元细胞外异常沉积形成的老年斑,二是 tau 蛋白的异常磷酸化所形成的 NFTs(神经元纤维缠结)但是,很多在大脑中出现淀粉样蛋白沉积的老年人并没有失智症症状。而与AD相关的记忆丧失和头脑混乱的症状与tau蛋白缠结相关。因此,近年来已有多种疗法试图靶向tau蛋白的产生和清除过程来治疗AD。日前在《Neuron》科学期刊上发表的最新研究表明,tau蛋白在神经细胞中的生成和分泌过程是一个主动的,受到调节的过程。这项发现可能帮助开发出基于靶向tau蛋白生成过程的AD疗法。

AD 患者脑中存在大量异常 Tau 蛋白。Tau 蛋白异常修饰、含量变化对临床 AD 病理发生有重要作用。Tau 蛋白异常磷酸化和异常糖基化相互作用促进 PHF/NFT 结构最终形成。

AD 患者脑组织切片上的沉淀斑块和神经元纤维缠结是 AD 的主要病理特征。因此沉淀斑块的主要组成 β-淀粉样蛋白以及纤维缠结的主要成分 tau 蛋白是目前 AD 研究的最主要方向。

由于采用 Aβ 通路作为靶点治疗轻至中度 AD 的临床试验相继以失败告终,tau 靶向药物,特别是 tau 聚集抑制剂对 AD 潜在的治疗作用越来越引人关注。以 Tau 通路作为靶点的治疗策略主要着重于限制引起 tau 蛋白早期聚集的病理性磷酸化。

基于 Tau 通路的药物开发策略:

1,通过 tau 稳定剂增强微管的稳定化

TPI.287 UCSF Microtubule stabilizer Stage I (ongoing) NCT01966666

2,通过 tau 蛋白聚集抑制剂防止 tau 蛋白的聚集

TRx0237,LMTM,第二代Tau聚集抑制剂 TauRx Therapeutics Tau aggregation ? Stage III (completed) ? NCT01689246
? Stage III (completed) ? NCT01689233
? Stage III (completed) ? NCT01626378
? Stage III (recruiting) ? NCT02245568

3,采用主动免疫疗法提高磷酸化 tau 蛋白的清除水平

AADvac.1 Axon Neuroscience SE Active vaccine, tau 294-305 Stage II (ongoing) NCT02579252
ACI35 AC Immune/ Janssen Active vaccine,16 copies of a tau fragment phosphorylated at S396/S404 (PHF1) Stage Ib (completed) ISRCTN13033912

4,对参与 Tau 蛋白转录后修饰的蛋白进行调控,阻止 Tau 蛋白的过度磷酸化

Saracatinib (AZD0530) AstraZeneca Src/Abl抑制剂, Fyn信号通路 Stage II (ongoing) NCT02167256
ANAVEX 273 Anavex σ1/muscarinic ligand Stage II (recruiting) NCT02756858

新格诺康产品:

正常 Tau 蛋白

Tau Protein Marker T08-07N
Tau-316 Protein T02-54N
Tau-352 Protein T03-54N
Tau-381 Protein T04-54N
Tau-383 Protein T05-54N
Tau-410 Protein T06-54N
Tau-412 Protein T07-54N
Tau-441 Protein T08-54N
Tau-441 Protein T08-54H
Tau-441, Biotinylated T08-54BN

突变 Tau 蛋白

Tau-383 (N352H) Protein T05-56N
Tau-441 (A152T) Protein T08-56VN
Tau-441 (dK280) Protein T08-52N
Tau-441 (dN296) Protein T08-52BN
Tau-441 (G272V) Protein T08-56DN
Tau-441 (K257T) Protein T08-56N
Tau-441 (L266V) Protein T08-56CN
Tau-441 (N279K) Protein T08-56EN
Tau-441 (P301L) Protein T08-56FN
Tau-441 (P301S) Protein T08-56GN
Tau-441 (R406W) Protein T08-56MN
Tau-441 (S198A) Protein T08-53BN
Tau-441 (S198E) Protein T08-53N
Tau-441 (S199E) Protein T08-53CN
Tau-441 (S214A) Protein T08-53DN
Tau-441 (S305N) Protein T08-56HN
Tau-441 (S352L) Protein T08-56KN
Tau-441 (S404A) Protein T08-53HN
Tau-441 (S404E) Protein T08-53GN
Tau-441 (V337M) Protein T08-56JN

截短的 Tau 蛋白

Tau-441 (1-391) Protein T08-55CN
Tau-441 (1-421) Protein T08-55BN
Tau-441 (127-421) Protein T08-55KN
Tau-441 (151-391) Protein T08-55FN
Tau-441 (151-421) Protein T08-55EN
Tau-441 (151-441) Protein T08-55DN
Tau-441 (216-391) Protein T08-55LN
Tau-441 (231-391) Protein T08-55IN
Tau-441 (231-421) Protein T08-55HN
Tau-441 (231-441) Protein T08-55GN
Tau-441 (244-372) Protein T08-55N
Tau-441 (244-372) Protein T08-55H
Tau-441 (244-372), Biotinylated T08-55NB
Tau-441 (50-391) Protein T08-55ON
Tau-441 (50-421) Protein T08-55NN
Tau-441 (50-441) Protein T08-55MN
Tau-441 (99-441) Protein T08-55JN

磷酸化的 Tau 蛋白

Tau-441, BRSK1-phosphorylated T08-50N
Tau-441, BRSK2-phosphorylated T08-50BN
Tau-441, CAMK2-phosphorylated T08-50CN
Tau-441, DYRK1A-phosphorylated T08-50RN
Tau-441, DYRK1A-phosphorylated & Biotinylated T08-50RNB
Tau-441, GSK3beta-phosphorylated T08-50FN
Tau-441, PHKG2-phosphorylated T08-50KN
Tau-441, PKA-phosphorylated T08-50LN
Tau-441, TTBK1-phosphorylated T08-50ON

抗 Tau 蛋白抗体

Anti-phospho-Tau (Ser214) T08-365GR
Anti-phospho-Tau (Ser235) T08-365FR
Anti-phospho-Tau (Ser262) T08-365IR
Anti-phospho-Tau (Ser356) T08-365MR
Anti-phospho-Tau (Ser396) T08-365ER
Anti-phospho-Tau (Ser404) T08-365HR
Anti-phospho-Tau (Ser416) T08-365DR
Anti-phospho-Tau (Ser422) T08-365KR
Anti-phospho-Tau (Thr181) T08-365R
Anti-phospho-Tau (Thr205) T08-365BR
Anti-phospho-Tau (Thr212) T08-365JR
Anti-phospho-Tau (Thr231) T08-365CR

一些主要的与 Tau 蛋白磷酸化相关的蛋白激酶

AKT1, Active A16-10G
AKT2, Active A17-10H
AKT3, Active A18-10G
CAMK1 beta, Active C08-10G
CAMK1 delta, Active C09-10G
CAMK1 gamma, Active C10-11G
CAMK1, Active C07-10G
CAMK2 alpha, Active C11-10G
CAMK2 beta, Active C12-10H
CAMK2 delta, Active C13-10G
CAMK2 gamma, Active C14-10G
CAMK4, Active C15-10G
CAMKK1, Active C17-10G
CAMKK2, Active C18-10G
CASK, Active C19-11G
CK1 alpha 1, Active C64-10G
CK1 alpha 1L, Active C75-10G
CK1 delta, Active C65-10G
CK1 epsilon, Active C66-10G
CK1 gamma 1, Active C68-11G
CK1 gamma 2, Active C68-10BG
CK1 gamma 3, Active C68-10CG
CK2 alpha 1, Active C70-10G
CK2 alpha 2, Active C71-10G
DAPK1, Active D01-11G
DAPK2, Active D02-10G
DAPK3, Active D03-10G
DYRK1A, Active D09-10G
DYRK1B, Active D09-10BG
DYRK2, Active D10-10G
DYRK3, Active D11-11G
DYRK4, Active D12-10G
ERK1, Active M29-10G
ERK2, Active M28-10G
ERK3 (MAPK6), Active M31-10G
ERK5, Active M32-10G
ERK7 (MAPK15), Active M47-10BG
FYN A, Active F15-10G
GSK3 alpha, Active G08-10G
GSK3 beta, Active G09-10G
GSK3 beta, Active G09-10H
JNK1, Active M33-10G
JNK2, Active M34-10BG
JNK3, Active M35-10BG
MARK1, Active M43-10G
MARK2, Active M44-10G
MARK3, Active M45-10G
MARK4, Active M46-10G
MEK1 (EE), Active M02-12G
MEK1, Active M02-10G
MEK2, Active M03-10G
MEK3 (MAP2K3), Active M04-10G
MEK4 (MAP2K4), Active M05-10G
MEK5, Active M06-10G
MEK6, Active M07-10G
MEK7, Active M08-10G
MELK, Active M50-11G
MELK, Active M50-18G
MINK1, Active M53-11G
MSK1, Active R19-10G
MSK2, Active R18-10G
MST1, Active S25-10G
MST3, Active S42-11G
MST4, Active M59-10G
p38 alpha, Active M39-10BG
p38 beta, Active M36-10BG
p38 delta, Active M38-10BG
p38 gamma, Active M37-10BG
PDK1, Active P14-10H
PIM1, Active P35-10G
PIM2, Active P36-10G
PIM3, Active P37-10G
PIM3, Active P37-10BG
PKAc alpha, Active P51-10G
PKAc beta, Active P52-10G
PKAc gamma, Active P53-10G
PYK2, Active P92-11H
RSK1, Active R15-10G
RSK2, Active R17-10G
RSK3, Active R16-10G
RSK4, Active R20-10G
TTBK1, Active T17-11G
TTBK2, Active T18-11G

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