Detection and Clearance of AD Amyloid Lesions

AD 淀粉样蛋白病变的检测和清除

• 批准号: 7323067
• 负责人: THOMAS M WISNIEWSKI
• 金额: $ 31.18万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7323067
• 关键词: APP-PS1; Active Immunization; Address; Adjuvant; Adverse effects; Affinity; Alzheimer' s disease model; Amyloid; Amyloid deposition; Animal Model; Animals; Antibodies; Antigens; Attenuated; Attenuated Vaccines; Autopsy; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Brain; Cellular Immunity; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Clinical; Clinical Trials; Cognitive; Data; Deposition; Detection; Development; Disease; Effectiveness; Elderly; Encephalitis; Funding; Gadolinium; Gastrointestinal tract structure; Grant; Hemorrhage; Human; Humoral Immunities; Immune response; Immunization; Inflammatory; Label; Lead; Lesion; Life; Ligands; Link; Lymphocytosis; Measurement; Methods; Microscopy; Modeling; Monitor; Monoclonal Antibodies; Mus; Numbers; Oral; Patients; Peptides; Peritoneal; Personal Satisfaction; Photons; Plasma; Population Control; Prevention; Principal Investigator; Prion Diseases; Production; Publishing; Reporting; Research Design; Risk; Role; Route; Salmonella; Salmonella Vaccines; Senile Plaques; Source; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic Effect; Tissues; Toxic effect; Transgenic Mice; Vaccinated; Vaccination; Vaccines; aluminum sulfate; cerebrovascular; concept; cytokine; design; improved; in vivo; mouse model; mucosal vaccination; novel; oral vaccine; prevent; response

DESCRIPTION (provided by applicant): In the initial funding period of this grant we first proposed the concept of a potentially safer vaccine approach for AD using A¿ homologous peptides which are non-toxic and non-fibrillogenic. In addition we pioneered the use of gadolinium labeled A¿3 ligands for in vivo detection of amyloid lesions in Tg AD mice. In this revised competing continuation we focus on our immunological approaches to bring them closer to potential clinical use. Extensive data from many groups has shown that in AD model animals vaccination against A(3 is an effective means of preventing amyloid deposition, in association with cognitive benefits. More limited data from the aborted human active vaccination trial suggests that this approach can lead to amyloid clearance and cognitive improvement. However encephalitis occurred in 6% of patients, which has been linked to excessive cell mediated immunity. In our further studies we plan to avoid this toxicity by using our non-toxic A¿ homologous peptides which have the T-cell epitopes removed or altered in conjunction with adjuvants that primarily stimulate a humoral immune response and are appropriate for human use. These include alum and Salmonella vaccine strains. A further potential toxicity linked with vaccination is hemorrhage associated with cerebral amyloid angiopathy (CAA), which we will address in our planned studies. This is an important issue as almost all AD patients at autopsy have CAA, with about 20% having severe CAA. The specific aims are: 1) Assess vaccination with two of our A¿ homologous immunogens using alum as an adjuvant in AD Tg models that either have predominantly parenchymal amyloid versus vascular amyloid deposition. Vaccination will be initiated at the start of deposition and also after deposition is established. 2) Assess mucosal vaccination using attenuated Salmonella expressing our A¿ homologous immunogens via an oral route. 3) Vaccinated animals will be characterized behaviorally. The amyloid burden will be determined as well as levels of soluble/insoluble/oligomeric A¿. In a subset of animals, whether clearance of existing amyloid deposits occurs will be determined in vivo using 2-photon microscopy. The Th-1 versus Th-2 response will be monitored by assessing cytokine production and specific antibody titers. Lay Summary: Active vaccination is an potential exciting therapy for AD; however, it can only be applied to patients if effective methods which are non-toxic can be developed. This application seeks to verify if this is possible.

描述（由应用程序提供）：在本赠款的初始资金期间，我们首先提出了使用无毒且非原纤维性的同源肽进行AD的潜在安全疫苗方法的概念。此外，我们还率先使用标记A 3配体的Gadolinium用于体内检测TG AD小鼠中淀粉样蛋白病变。在经过修订的竞争延续中，我们着重于我们的免疫学方法，使它们更接近潜在的临床用途。来自许多小组的大量数据表明，在AD模型中，动物接种A（3是一种与认知益处相关的有效手段，可以预防淀粉样蛋白沉积。从中流产的人类活性疫苗试验中，来自中断的人类活性疫苗试验的数据表明，这种方法可以导致淀粉样蛋白的清除率和认知能力改善。但是，该细胞的跨性别是在我们的6％中与我们之间的跨性别性有关，以避免在我们的6％中，我们避免了我们在我们的6％中避免了我们在我们的范围内，这是我们避免的，这是我们的避免症状，以避免在我们的6％中，避免了我们的跨性别症。通过使用我们的非毒性A的毒性，其具有T细胞表位的毒性与刺激体外免疫的结合，将其与人类使用相关的氧化和杂种疫苗相关。我们计划的研究是一个重要的问题，因为几乎所有尸检的AD患者都有CAA，大约有20％的CAA。具体目的是：1）使用明矾作为AD TG模型的调整，用我们的两种同源免疫原子评估疫苗，该模型主要具有副型淀粉样蛋白淀粉样蛋白与血管淀粉样蛋白的沉积。疫苗接种将在沉积开始和建立沉积后开始。 2）使用衰减的沙门氏菌评估粘膜疫苗接种，通过口服途径表达我们的同源免疫原。 3）疫苗接种的动物将以行为为特征。淀粉样蛋白燃烧以及固体/不溶性/寡聚的水平将确定。在动物的一部分中，使用2光子显微镜在体内确定现有淀粉样蛋白沉积物的清除。将通过评估细胞因子的产生和特定抗体滴度来监测TH-1与TH-2反应。摘要摘要：主动疫苗接种是AD的潜在令人兴奋的疗法；但是，只有可以开发出无毒的有效方法，才能应用于患者。该应用程序旨在验证是否可能。