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：
8426117
负责人：
Elizabeth Head
金额：
$ 28.31万
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8426117
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 cognitive impairment mouse model neurogenesis neuron loss neuropathology neurotrophic factor normal aging novel prevent research study response sex social

项目摘要

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.

阿尔茨海默病（AD）与进行性认知能力下降和老年痴呆症的积累有关。斑块和神经原纤维缠结老年斑含有 β-淀粉样肽 (A¿)，被认为是因此，正在开发许多可以减少这种疾病的治疗方法。生产、沉积或增强A¿的清除在 AD 患者的转基因小鼠大脑中。 AD 模型，A¿ 沉积使用原纤维 A 免疫后可以预防或减少进一步地，1-42。主动或被动免疫抗A¿可改善学习和记忆上的抗体。在转基因小鼠工作的基础上，在 AD 患者中启动了一项临床试验（AN1792）纤维状A¿ 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自然老化的犬类模型中人类A型??老年动物积极免疫超过 2 年（注射 25 次）。我们对免疫的老年比格犬的结果显示大脑 A 减少。并改善执行功能。我们追求的是能够更大程度的提高认知，并将认知的提升延伸到通过联合治疗和干预来涵盖多个领域，这可能会在 A¿ 后恢复神经系统健康因此，我们建议将免疫疗法与老年犬和目标的行为富集相结合。我们预测老年狗将表现出两种分子途径的结合，从而提供额外的益处。当我们结合使用时，显着的认知改善、认知维持和神经病理学减少此外，联合治疗将为患者带来更大的益处。与单独治疗相比，犬科动物提供了一个独特的模型系统。开发涉及免疫疗法的组合治疗方法，以减少 AD 病理学和改善认知可能更直接地转化为人体临床试验。