Therapeutic Targeting of Abnormal Conformation in Neurodegenerative Disease

描述（由申请人提供）：许多神经退行性疾病的特征是自身蛋白的构象改变为淀粉样蛋白，病理构象，它们具有结构特性，如高¿-sheet含量和抗降解性。阿尔茨海默病（AD）是最常见的神经退行性蛋白构象疾病，包括弥漫性路易体病（DLBD）、帕金森病（PD）、朊病毒病和额颞叶变性（FTLD）。毒性最大的构象是低聚构象。这些构象性疾病都没有有效的治疗方法；然而，免疫调节对阿尔茨海默病和朊病毒疾病都显示出巨大的希望。这种方法的主要问题包括：脑炎的潜在毒性（与过度的细胞介导免疫有关），正常和异常A¿的免疫靶向，血管淀粉样蛋白对清除的抵抗，以及tau相关的病理没有得到具体解决。本提案的中心假设是，这些限制都可以通过特异性靶向异常低聚物构象和开发新方法来克服，以防止低聚物介导的毒性。我们新颖的主动免疫调节方法使用了一种聚合的英国淀粉样变性（pABri）相关肽，主要是一种低聚形式。我们假设，通过“构象模仿”，聚合的ABri肽可以诱导构象选择性免疫反应，识别a¿和构象异常的tau。APP/PS1 AD小鼠模型的初步数据支持了这一假设。这种免疫刺激方法应该降低诱导自身免疫并发症的风险，因为它对病理构象更具特异性，而且免疫原与任何已知的哺乳动物蛋白/肽没有序列同源性。我们还提供了初步数据，表明短期使用抗prp抗体单克隆6D11治疗可以逆转AD模型APP/PS1 Tg小鼠的行为缺陷。该抗体阻断A¿寡聚物与PrPC的结合。我们假设阻断A¿寡聚物和PrPC的结合是一种新的治疗AD的策略。这些互补的方法旨在增加A¿低聚物的清除率，并特异性地阻断其毒性。

DESCRIPTION (provided by applicant): Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ¿-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms. None of the conformational diseases has an effective therapy; however, immunomodulation has shown great promise for both AD and prion diseases. Major problems with this approach include: the potential of toxicity from encephalitis (related to excessive cell mediated immunity), the immunological targeting of both the normal and abnormal A¿, the resistance of vascular amyloid to clearance, as well as tau related pathology not being specifically addressed. The central hypothesis of this proposal is that each of these limitations can be overcome by specific targeting of abnormal oligomer conformation and development of novel methods to prevent oligomer mediated toxicity. Our novel active immunomodulation approach uses a polymerized British amyloidosis (pABri) related peptide in a predominantly ¿-sheet, oligomeric form. We hypothesized that through "conformational mimicry" the polymerized ABri peptide could induce a conformation selective immune response that will recognize both A¿ and conformationally abnormal tau. This hypothesis is supported by preliminary data in an APP/PS1 AD mouse model. Such an immunostimulatory approach should have a reduced risk of inducing auto-immune complications as it is more specific to a pathological conformer and the immunogen has no sequence homology to any known mammalian protein/peptide. We also present preliminary data that short term treatment with monoclonal 6D11, an anti-PrP antibody, reverses behavioral deficits in an AD model APP/PS1 Tg mice. This antibody blocks the binding of A¿ oligomers to PrPC. We hypothesize that blocking the binding of A¿ oligomers and PrPC is a novel therapeutic strategy for AD. These complementary approaches will aim to both increase clearance of A¿ oligomers and specifically block their toxicity.