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构象变化为淀粉样变性的病理构象，这些构象具有高折叠含量和抗降解等结构特性。阿尔茨海默病(AD)是最常见的神经退行性蛋白构象障碍，包括弥漫性路易体病(DLBD)、帕金森病(PD)、普恩病毒病和额颞叶变性(FTLD)。毒性最强的构象是低聚形式。没有一种构象疾病有有效的治疗方法；然而，免疫调节对阿尔茨海默病和普鲁恩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(与过度的细胞免疫有关)，正常和异常的Aé的免疫学靶点，血管淀粉样蛋白对清除的抵抗力，以及tau相关的病理没有被具体解决。这一建议的中心假设是，通过针对异常低聚物构象的特定靶向和开发新的方法来防止低聚物介导的毒性，可以克服这些限制。我们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)相关多肽，以片状、低聚形式为主。我们推测，通过“构象模拟”，聚合的ABRI多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可以降低诱发自身免疫并发症的风险，因为它更针对病理构象，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。我们还提供了初步数据，抗PrP单抗6D11短期治疗可以逆转AD模型APP/PS1 TG小鼠的行为缺陷。该抗体可阻断A？寡聚体与PrPC的结合。我们推测，阻断A？寡聚体与PrPC的结合是AD的一种新的治疗策略。这些相辅相成的方法将旨在增加低聚体的清除量，并特别阻止它们的毒性。

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.