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(由申请人提供)：到2050年，阿尔茨海默病(AD)的患病率可能在全球范围内翻两番，但目前还没有有效的治疗方法。AD标志性病变是由A�多肽和磷酸化tau(p-tau)缠结组成的斑块。[�免疫已经有效地消除了它在大脑中的靶标，即使在AD患者中也是如此，尽管其有效性和试验设计仍然存在问题。肌萎缩侧索硬化症与阿尔茨海默病的记忆力下降有很好的相关性，也是其他肌萎缩侧索硬化症的一个定义特征。此外，针对p-tau缠结表位或tau种子的主动或被动免疫在小鼠模型中显示出良好的效果。然而，由于神经元功能障碍早在缠结形成之前，针对导致AD记忆丧失的早期致病椒盐事件的免疫治疗正在积极进行。]值得注意的是，阿尔茨海默病的早期事件是tau过度磷酸化，特别是在Ser/Thr-Pro基序上。我们以前已经发现tau(pT231-tau)中的磷酸化Thr231-Pro基序存在于顺式和反式构象中，并鉴定了独特的Prolyl异构酶Pin1来加速它们的转换，以防止p-tau的错误折叠和抑制转位。此外，在人类MCI和AD神经元中，Pin1被多种机制抑制，而阻止其下调的Pin1 SNP与延迟AD发病有关。此外，人类Pin1基因位于19p13.2，与迟发性AD相关，pT231-tau位于AD角神经元中连续的p-tau表位的起始位置，而脑脊液中的pT231-tau与记忆丧失相关，并跟踪MCI向AD的转化。这些结果表明，pT231-tau在AD中是一个非常早期的致病事件。[我们最近开发了一种新的技术来产生第一个顺式和反式pT231-tau多克隆抗体，并鉴定了以前未发现的导致MCI和AD的牛磺酸病变的早期致病顺式tau。我们现在创造了中和性单抗，在体外、体外和小鼠体内有效地清除了这种早期的、分泌的和有毒的顺式tau。因此，这项建议旨在检验我们的新假设，即中和构象特异性单抗和疫苗只针对早期、分泌和毒性的顺式p-tau，而不接触健康的反式可能在阻止甚至预防AD的转位方面高效和特异。目的1进一步确定最佳的顺式和反式单抗，并评价其在体外和体外中和p-tau诱导和传播神经毒性的效果和机制。目的2将评估顺式和反式pT231-tau单抗对两种不同但互补的直立性病变小鼠模型的影响。目的3将开发和评估顺式和反式pT231-tau疫苗对两种肌病小鼠模型的治疗效果。预期的结果将构成针对早期、分泌和毒性顺式pT231-tau的创新构象特异性免疫疗法，为早期停止或预防AD患者的肌病和记忆丧失提供独特的机会。这项研究可以为针对AD早期致病错误折叠蛋白的治疗提供一种独特的方法。]