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质的构象变化为淀粉样蛋白生成的病理性构象，它们具有相同的结构特性，例如高的à-片含量和抗降解性。阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性蛋白质构象障碍，包括弥漫性路易体病（diffuse Lewy body disease，DLBD）、帕金森病（Parkinson's disease，PD）、朊病毒病（prion diseases）和额颞叶变性（frontotemporal lobar degeneration，FTLD）。毒性最大的构象是低聚物形式。构象性疾病都没有有效的治疗方法，然而，免疫调节对AD和朊病毒疾病都显示出很大的希望。这种方法的主要问题包括：脑炎的潜在毒性（与过度的细胞介导的免疫有关）、正常和异常A的免疫靶向、血管淀粉样蛋白对清除的抗性以及未被具体解决的tau相关病理学。该建议的中心假设是，这些限制中的每一个都可以通过特异性靶向异常寡聚体构象和开发新方法来防止寡聚体介导的毒性来克服。 我们的新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，主要是一种寡聚体形式。我们假设通过“构象模拟”，聚合的ABri肽可以诱导构象选择性免疫应答，该应答将识别A？和构象异常的tau。APP/PS1 AD小鼠模型中的初步数据支持该假设。这样的免疫刺激方法应该具有降低的诱导自身免疫并发症的风险，因为它对病理构象异构体更特异，并且免疫原与任何已知的哺乳动物蛋白质/肽没有序列同源性。我们还提出了初步的数据，短期治疗与单克隆6D 11，抗PrP抗体，逆转AD模型APP/PS1 Tg小鼠的行为缺陷。该抗体阻断A？寡聚体与PrPC的结合。我们假设阻断A？寡聚体和PrPC的结合是AD的一种新的治疗策略。这些补充方法旨在增加A？寡聚体的清除率并特异性阻断其毒性。

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.