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：
8037033
负责人：
Elizabeth Head
金额：
$ 71.42万
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/8037033
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 S-nitro-N-acetylpenicillamine 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 drebrins 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 research study response sex social

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（由适用提供）：阿尔茨海默氏病（AD）与进行性认知能力下降以及老年斑块和神经原纤维缠结的积累有关。老年斑块中包含β-淀粉样蛋白肽（A a），被认为在该疾病中起因作用。这是正在开发许多治疗剂，可以减少AD患者大脑中A的产生，沉积或增强A的清除。在AD的转基因小鼠模型中，可以用原纤维a¿1-42免疫后A a的沉积。此外，通过抗A抗体的主动或被动免疫抑制可以改善学习和记忆。根据转基因小鼠的工作，在接受纤维纤维a¿42的AD患者中启动了一项临床试验（AN1792）。在这项研究中报道了认知益处，尸检研究表明大脑a ath的降低。我们将免疫疗法研究扩展到了自然发展人类型和认知能力下降的人脑衰老的犬类模型。老年动物积极免疫2年以上（总共25例）。我们在免疫的老年蛋糕中的结果显示出降低的大脑a a。并改善了执行功能。我们假设我们可以在更大程度上提高认知，并扩大认知改善，从而通过将治疗和干预措施组合在一起，该干预措施可以恢复A ememe a ememe的神经元健康。我们建议将免疫疗法与老年狗的行为富集结合起来，并靶向两种分子途径，以融合以提供额外的好处。我们预测，当我们将免疫疗法与行为富集相结合时，老年狗将显示出显着的认知改善，认知的维持和降低的神经病理学。此外，组合治疗将为认知和神经病理学带来更大的好处，而不是单独治疗。犬提供了一个独特的模型系统，在其中开发涉及免疫疗法的组合治疗方法，以减少AD病理学和改善认知，这可能会更直接地转化为人类临床试验。公共卫生相关性：阿尔茨海默氏病（AD）与进行性认知能力下降和脑病理的积累有关。我们将使用一种联合治疗方法来改善通过免疫疗法和行为酶衰老的犬种模型中的认知和神经病理学，这是一种可以直接转化为人类临床试验的方法。