Therapeutic Targeting of Abnormal Conformation in Neurodegenerative Disease

神经退行性疾病异常构象的治疗靶向

基本信息

批准号：
9097810
负责人：
THOMAS M WISNIEWSKI
金额：
$ 37.08万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097810
关键词：
APP-PS1 Abrus Active Immunization Affect Affinity Age Alzheimer disease prevention Alzheimer&apos s Disease Amyloid Amyloidosis Antibodies Binding Blood Vessels British Clinical Trials Data Deposition Disease Down Syndrome Encephalitis Funding Glutaral Grant Health Hemorrhage Human Image Immune Immune response Immunization Immunotherapy Lesion Lewy Bodies Lewy Body Disease Measurement Mediating Mediator of activation protein Methods Modeling Molecular Conformation Monoclonal Antibodies Mus Natural Immunity Neurodegenerative Disorders Neurofibrillary Tangles Passive Immunization Pathology Peptides PrPSc Proteins Preparation Preventive Proteins Proteomics Resistance Seeds Senile Plaques Staging Surface Plasmon Resonance TLR9 gene Testing Tg2576 Therapeutic Tissues Toxic effect Transgenic Mice Vascular resistance Western Blotting abeta oligomer alpha synuclein beta pleated sheet biophysical properties conformer cytotoxicity extracellular human tissue in vivo laser capture microdissection mimicry mouse model neurotoxicity novel pre-clinical preclinical study prion-like protein TDP-43 protein aggregate protein aggregation tau Proteins tau aggregation tau conformation tau-1 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease [AD] is characterized by Aß amyloid deposits in the form of extracellular amyloid ß (Aß) plaques and tau protein aggregates in the form of intracellular neurofibrillary tangles (NFT). Soluble oligomeric forms of Aß and tau are the chief mediators of cytotoxicity in AD. Preclinical studies in transgenic mouse models have shown great efficacy of Aß targeting immunotherapy in the prevention of AD but clinical trials have so far failed to show benefits. We plan to test the hypothesis that for therapy to be effective the concurrent targeting of both Aß and tau related pathology is essential. Our novel active immunization approach uses a polymerized peptide derived from the carboxyl terminus of the British amyloidosis (ABri) peptide prepared by the use of glutaraldehyde as a cross linker, that results in a stabilized, predominately ß sheet oligomeric form that does not form fibrils, which we term pBri. We showed that via conformational mimicry, the pBri peptide, in its stabilized oligomeric form, can initiate a conformation selective immune response, which is specific to pathological aggregated/oligomeric conformers of phosphorylated tau and Aß. In the last funding period we have also shown that stimulation of innate immunity via TLR9 can reduce plaques and tau pathology in Tg2576 and 3xTg mice. The specific aims are: 1) Test conformation targeted active immunization with pBri in htau/PS1 Tg and Tg4510 mice with extensive NFT pathology, as well as in a model of Lewy body pathology (tTA/A53Ta-syn) in order to determine if our novel active immunization approach is effective against tau and a- synuclein related pathology. 2) Characterize our panel of monoclonal anti-pathological conformation antibodies using human tissue, Western blots, laser capture microdissection and surface plasmon resonance measurements. The best mAb will be tested in Tg mouse models. 3) We will determine if our method of stimulating innate immunity via TLR9 with CpG is effective at ameliorating vascular amyloid in TgSwDI mice and tau pathology in Tg4510 mice. These planned studies will provide essential data on three therapeutic approaches that concurrently target Aß and tau pathology prior to potential testing in humans.

描述（由适用提供）：阿尔茨海默氏病[AD]的特征是Aß淀粉样蛋白沉积物的形式为细胞外淀粉样蛋白斑（Aß）斑块（Aß）斑块和Tau蛋白聚集体，以细胞内神经纤维纤维缠结（NFT）的形式形式。 Aß和Tau的可溶性低聚形式是AD中细胞毒性的主要介体。转基因小鼠模型中的临床前研究表明，Aß靶向免疫疗法在预防AD方面的有效性很高，但到目前为止，临床试验未能显示出好处。我们计划检验以下假设：要使治疗有效地靶向Aß和TAU相关的病理学是必不可少的。我们新型的主动免疫抑制方法使用了通过使用戊二醛作为交叉连接器制备的英国淀粉样变性（ABRI）肽的聚合肽（ABRI）肽，从而导致稳定，主要是β柔软的形式，而不是形成Fibibrils pribibrils pribirls，pri termpbri。我们表明，通过构象模仿，以其稳定的寡聚形式的PBRI肽可以启动构象选择性免疫反应，这是针对磷酸化的tau和Aß的病理聚集/寡聚构象异构体。在最后的资金期间，我们还表明，通过TLR9刺激先天免疫学可以减少TG2576和3XTG小鼠中的斑块和TAU病理。具体目的是：1）测试会议针对HTAU/PS1 TG中的PBRI和具有广泛NFT病理学的TG4510小鼠的主动免疫学，以及在Lewy身体病理学模型（TTA/A53TA-SYN）模型中，以确定我们的新型活性免疫学是否有效地抗tau和A- syncylogicy。 2）表征我们的单克隆抗病理构象抗体，使用人体组织，蛋白质印迹，激光捕获显微解剖和表面等离子体共振测量。最好的mAB将在TG鼠标模型中进行测试。 3）我们将确定我们通过CPG通过TLR9刺激先天免疫学的方法有效地改善TGSWDI小鼠中TG4510小鼠的TGSWDI小鼠和TAU病理学的血管淀粉样蛋白。这些计划的研究将提供有关三种治疗方法的基本数据，这些方法在人类进行潜在测试之前同时针对Aß和TAU病理。