Beta-Amyloid Immunization in a Canine Model of Aging

犬衰老模型中的β-淀粉样蛋白免疫

基本信息

批准号：
7777861
负责人：
Elizabeth Head
金额：
$ 70.32万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777861
关键词：
12 year old AN-1792 Active Immunization Adjuvant Adverse event Affect Aftercare Age Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Animal Model Animals Antibodies Antigens Attenuated Autopsy B-Lymphocytes Behavioral Biological Models Brain Brain Pathology Brain-Derived Neurotrophic Factor Bromodeoxyuridine Canis familiaris Cerebral Amyloid Angiopathy Clinical Trials Cognition Cognitive Combined Modality Therapy Congo Red Data Deposition Discrimination Discrimination Learning Disease Dot Immunoblotting Dynamin I Enzyme-Linked Immunosorbent Assay Excision Exercise Experimental Designs Female Future GDNF gene Growth Factor Head Health Hippocampus (Brain)Housing Human Immune response Immunization Immunotherapy Impaired cognition Individual Infiltration Injection of therapeutic agent Intervention Lead Learning Maintenance Matched Group Measures Mediating Memory Memory impairment Methods Modeling Molecular NR2B NMDA receptor Neurofibrillary Tangles Neurons Neuropsychological Tests Outcome Outcome Measure Outcome Study Passive Immunization Pathogenesis Pathology Pathway interactions Patients Phase Play Polysorbate 80 Procedures Production Proteins Prussian blue Publishing Reagent Relative (related person)Reporting Reversal Learning Role Sampling Senile Plaques Synapses Synaptophysin T-Lymphocyte Techniques Testing Therapeutic Time Tissues Toy Transgenic Mice Translating Visual Walking Western Blotting Work aged aging brain aluminum sulfate base cognitive function cognitive training combinatorial design disability environmental enrichment for laboratory animals executive function improved improved functioning male mild neurocognitive impairment mouse model neurogenesis neuron loss neuropathology neurotrophic factor normal aging novel prevent public health relevance research study response sex social visual learning

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A¿), which is thought to play a causative role in the disease. Thus, a number of therapeutics are being developed that may reduce the production, deposition or enhance clearance of A¿ in the brains of patients with AD. In transgenic mouse models of AD, deposition of A¿ may be prevented or reduced after immunization with fibrillar A¿1-42. Further, learning and memory is improved by either active or passive immunization with anti-A¿ antibodies. On the basis of work in transgenic mice, a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A¿42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A¿. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A¿ and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A¿ and improved executive function. We hypothesize that we can improve cognition to a greater extent, and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A¿ removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements, maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further, the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment, which is an approach that may be directly translated into human clinical trials.

描述（由申请人提供）：阿尔茨海默氏病 (AD) 与进行性认知能力下降以及老年斑和神经原纤维缠结的积累有关。老年斑含有 β-淀粉样肽 (A¿)，人们认为它在其中发挥着致病作用。因此，正在开发许多可以减少 A¿ 的产生、沉积或增强清除的治疗方法。在 AD 转基因小鼠模型中，A¿ 沉积在 AD 患者的大脑中。使用原纤维 A 免疫后可以预防或减少1-42 此外，主动或被动免疫抗 A¿ 可以改善学习和记忆。在转基因小鼠研究的基础上，在接受原纤维 A¿ 治疗的 AD 患者中启动了一项临床试验 (AN1792)。 42. 这项研究报告了认知益处，尸检研究表明大脑 A 减少我们将免疫疗法研究扩展到人类大脑衰老的犬类模型中，该模型自然形成人类 A 型大脑。老年动物积极免疫超过 2 年（总共注射 25 次），结果显示老年比格犬的大脑 A 下降。我们追求的是，我们可以在更大程度上改善认知，并将认知改善扩展到多个领域，通过将治疗与可能在 A 后恢复神经健康的干预措施相结合。因此，我们建议将免疫疗法与老年犬的行为丰富化相结合，并针对两种可能汇聚以提供附加益处的分子途径。我们预测，当我们将免疫疗法与行为丰富化相结合时，老年犬将表现出显着的认知改善、认知维持和神经病理学减少。此外，与单独的治疗相比，联合治疗将为认知和神经病理学提供更大的益处，犬科动物提供了一个独特的模型系统，在该系统中开发涉及免疫疗法的组合治疗方法，以减少 AD 病理并改善认知，这可以更直接地转化为认知。公共健康相关性：阿尔茨海默氏病（AD）与进行性认知衰退和大脑病理积累有关，我们将通过免疫疗法和行为丰富，在犬类衰老模型中使用联合治疗方法来改善认知并减少神经病理。，这是一种可以直接转化为人体临床试验的方法。