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

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，但目前尚无有效的治疗方法。AD的标志性病变是由Aβ肽和磷酸化tau （p-tau）缠结形成的斑块。即使在阿尔茨海默病患者中，Aβ免疫也有效地消除了大脑中的靶点，尽管其有效性和试验设计仍存在问题。牛头病与阿尔茨海默病的记忆力下降密切相关，也是其他牛头病的一个决定性特征。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有希望的效果。然而，由于神经功能障碍早于缠结形成，因此针对导致AD患者记忆丧失的早期致病性缠结前事件的免疫疗法正在积极研究中。值得注意的是，阿尔茨海默病的早期事件是tau蛋白过度磷酸化，特别是在Ser/Thr-Pro基序上。我们之前已经发现tau蛋白中磷酸化的Thr231-Pro基序（pT231-tau）以顺式和反式构象存在，并且还发现了独特的脯氨酸异构酶Pin1来加速它们的转化，以防止p-tau错误折叠并抑制tau病。此外，Pin1在人类MCI和AD神经元中受到多种机制的抑制，而阻止其下调的Pin1 SNP与AD的延迟发病有关。此外，人类Pin1位于19p13.2与迟发性AD相关，pT231-tau位于AD前缠结神经元序列p-tau表位的开始，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是阿尔茨海默病的一个非常早期的疾病起始事件。我们最近开发了一种新技术来产生首个顺式和反式pT231-tau多克隆抗体，并鉴定了以前未被识别的导致MCI和AD中tau病变的早期致病性顺式tau。我们现在创造了中和mAb，在体外、离体和小鼠体内有效地去除这种早期、分泌和有毒的顺式tau。因此，这一提议旨在验证我们的新假设，即中和构象特异性单克隆抗体和疫苗仅针对早期，分泌和有毒的顺式p-tau，而不影响健康的反式，可能在阻止甚至预防AD的tau病方面是高效和特异性的。目的1将进一步确定最佳的顺式和反式单抗，并评估其在体外和离体中和p-tau诱导和传播神经毒性的能力方面的功效和机制。目的2将在两种不同但互补的小鼠tau模型中评估顺式和反式pT231-tau单克隆抗体对tau病的影响。目的3将开发和评估顺式和反式pT231-tau疫苗对两种牛头病小鼠模型的牛头病的影响。预期的结果将构成创新的构象特异性免疫疗法，针对tau病变中非常早期、分泌和有毒的顺式pT231-tau，为阻止或预防早期AD患者的tau病变和记忆丧失提供独特的机会。这项研究可以为针对阿尔茨海默病早期致病性错误折叠蛋白的治疗提供一种独特的方法。

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 Aβ peptides and tangles of phosphorylated tau (p-tau). [Aβ 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.]