Drug Discovery against the Early, Secreted and Toxic Tau in Alzheimer's Disease

针对阿尔茨海默病早期、分泌性和毒性 Tau 蛋白的药物发现

• 批准号: 9272352
• 负责人: Kun Ping Lu
• 金额: $ 35.67万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272352
• 关键词: 19p13.2; Active Immunization; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Apoptosis; Attention; Biological Markers; Brain; Brain Diseases; Cell model; Chemistry; Cognitive deficits; Development; Disease; Down-Regulation; Epitopes; Event; Human; Hybridomas; Immunization; Immunize; Immunotherapy; In Vitro; Injury; Isomerism; Late Onset Alzheimer Disease; Lead; Memory Loss; Memory impairment; Microtubules; Molecular Conformation; Monoclonal Antibodies; Mus; Mutation; Neurites; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Onset of illness; Outcome; Passive Immunization; Pathogenicity; Pathology; Patients; Peptides; Peptidylprolyl Isomerase; Phosphopeptides; Prevalence; Protein Dephosphorylation; Research; Resistance; Stress; Tauopathies; Testing; Therapeutic; Time; Toxic effect; Traumatic Brain Injury; Vaccines; design; drug discovery; effective therapy; efficacy trial; improved; in vivo; innovation; misfolded protein; mouse model; neurofibrillary tangle formation; neuron loss; neuropathology; neurotoxicity; neutralizing antibody; neutralizing monoclonal antibodies; neutralizing vaccine; new technology; novel; overexpression; plaque lesion; polyclonal antibody; prevent; public health relevance; tau Proteins; tau aggregation; tau-1; trial design

DESCRIPTION (provided by applicant): Prevalence of Alzheimer's disease (AD) may quadruple worldwide by 2050, but there is no effective treatment available. The AD hallmark lesions are plaques made of A� peptides and tangles of phosphorylated tau (p-tau). [A� immunization has effectively eliminated its target in brains even in AD patients, albeit questions remain about its efficacy and trial design. Tauopathy correlates well with memory decline in AD and also is a defining feature of other tauopathies. Moreover, active or passive immunization against p-tau tangle epitopes or tau seeding shows promising efficacy in mouse models. However, since neuronal dysfunction long precedes tangle formation, immunotherapies specifically against the early pathogenic pretangle events that lead to memory loss in AD are being actively pursued.] Notably, an early event in AD tauopathy is tau hyperphosphorylation especially on Ser/Thr-Pro motifs. We have previously found that the phosphorylated Thr231-Pro motif in tau (pT231-tau) exists in the cis and trans conformations, and also identified the unique prolyl isomerase Pin1 to accelerate their conversion to prevent p-tau misfolded and inhibit tauopathy. Furthermore, Pin1 is inhibited by multiple mechanisms in human MCI and AD neurons, whereas the Pin1 SNP that prevents its down-regulation is associated with delayed AD onset. In addition, human Pin1 is located at 19p13.2 associated with late-onset AD pT231-tau is at the beginning of sequential p-tau epitopes in AD pretangle neurons and pT231-tau in CSF correlates with memory loss and tracks MCI conversion to AD. These results suggest that pT231-tau is a very early disease-initiating event in AD. [We have recently developed a novel technology to generate the first cis and trans pT231-tau polyclonal antibodies, and identified the previously unrecognized early pathogenic cis tau that leads to tauopathy in MCI and AD. We now created neutralizing mAb that effectively removed this early, secreted and toxic cis tau in vitro, ex vivo and in mice. Thus, this proposal is designed to test our novel hypothesis that neutralizing conformation-specific mAbs and vaccines against only the early, secreted and toxic cis p-tau while leaving the healthy trans untouched may be highly efficacious and specific in halting or even preventing tauopathy in AD. Aim 1 will further identify the best cis and trans mAbs and evaluate their efficacy and mechanisms in neutralizing the ability of p-tau to induce and spread neurotoxicity in vitro and ex vivo. Aim 2 will evaluate the effects of cis and trans pT231-tau mAbs on tauopathy in two different but complementary mouse models of tauopathy. Aim 3 will develop and evaluate the effects of cis and trans pT231-tau vaccines on tauopathy in two mouse models of tauopathy. The expected outcomes would constitute innovative conformation-specific immunotherapies against the very early, secreted and toxic cis pT231-tau in tauopathy, raising the unique opportunity of halting or preventing tauopathy and memory loss in AD patients at early stages. This research can offer a unique approach for therapeutics directed specifically against the early pathogenic misfolded proteins in AD.]

描述（由适用提供）：到2050年，阿尔茨海默氏病（AD）的患病率可能四倍，但没有有效的治疗方法。 AD标志性病变是由磷酸化TAU（P-TAU）的肽和缠结制成的斑块。 [A.免疫抑制即使在AD患者中，也有效地消除了其在大脑中的目标，尽管其有效性和试验设计仍然存在问题。 Tauopathy与AD的记忆下降良好相关，也是其他Tauopathies的定义特征。此外，针对P-TAU缠结表位或Tau播种的主动或被动免疫抑制在小鼠模型中显示出希望的有效性。然而，由于神经元功能障碍长期以来一直在缠结形成之前，因此针对早期的病原甲状腺肿事件的免疫疗法正在积极追求。我们先前已经发现，在CIS和翻译中存在磷酸化的THR231-PRO基序（PT231-TAU），并且还鉴定出独特的蛋白酶异构酶PIN1，以加速其转化率以防止P-TAU折叠率失误并抑制tauopathy。此外，PIN1受到人MCI和AD神经元中多种机制的抑制，而PIN1 SNP防止其下调与延迟的AD发作有关。此外，人类PIN1位于19p13.2与后期发作的AD PT231-TAU相关的AD PRETANGLE神经元中的顺序P-TAU表位开始时，CSF中的PT231-TAU与内存损失相关，并跟踪MCI转换为AD。这些结果表明，PT231-TAU是AD中非常早期的疾病引发事件。 [我们最近开发了一种新型技术，可以生成第一个顺式和反式PT231-TAU多克隆抗体，并确定了先前未识别的早期致病性顺式Tau，该病原体导致MCI和AD中的Tauopathy。现在，我们创建了中和mab，在体外，体内和小鼠中有效地有效地消除了这一早期，分泌和有毒的顺式tau。该提案旨在检验我们的新假设，即仅针对早期，分泌和有毒的顺式p-tau中和中和会议特异性的单克管和疫苗，同时离开健康的反式不受欢迎的trans不变的效率可能是高效且特异性的，甚至可以阻止AD中的tauopathy。 AIM 1将进一步识别最佳的顺式和反式mab，并评估它们在中和p-tau在体外和离体中诱导和传播神经毒性的能力方面的有效性和机制。 AIM 2将评估在两种不同但完整的Tauopathy小鼠模型中，顺式和反式PT231-TAU mAb对tauopathy的影响。 AIM 3将在两种小鼠tauopathy模型中开发和评估顺式和反式PT231-TAU疫苗对tauopathy的影响。预期的结果将构成针对大疾病中早期，分泌和有毒的顺式PT231-TAU的创新会议特异性免疫疗法，从而增加了在早期阶段停止或防止AD患者的Tauopathy和AD患者记忆力丧失的独特机会。这项研究可以提供一种独特的方法，专门针对AD中早期病原性错误折叠的蛋白质。]