Beta-Amyloid Immunization in a Canine Model of Aging

描述（由申请人提供）：阿尔茨海默病（AD）与进行性认知能力下降、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¿），它被认为在疾病中起着致病作用。因此，许多治疗方法正在开发中，可能会减少AD患者大脑中a¿的产生、沉积或增强其清除。在AD转基因小鼠模型中，原纤维A¿1-42免疫后可阻止或减少A¿的沉积。此外，抗a抗体的主动或被动免疫都能改善学习和记忆。在转基因小鼠工作的基础上，在给予纤维a¿42的AD患者中启动了一项临床试验（AN1792）。这项研究报告了认知方面的好处，解剖研究表明，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，这些模型自然发展为人类A型血和认知能力下降。老龄动物主动免疫2年以上（共注射25针）。我们的研究结果显示，接种过疫苗的老年小猎犬的大脑A¿减少了，执行功能得到了改善。我们假设我们可以在更大程度上改善认知，并通过联合治疗和干预将认知改善扩展到多个领域，这些干预可能会在a¿去除后恢复神经元的健康。因此，我们建议将老年犬的免疫治疗与行为富集相结合，并针对可能收敛的两种分子途径提供附加益处。我们预测，当我们将免疫疗法与行为富集相结合时，老年狗将表现出显著的认知改善、认知维持和神经病理减少。此外，与单独治疗相比，联合治疗将为认知和神经病理学提供更大的益处。犬类提供了一个独特的模型系统，用于开发包括免疫疗法在内的联合治疗方法，以减少AD病理和改善认知，这可能更直接地转化为人类临床试验。公共卫生相关性：阿尔茨海默病（AD）与进行性认知能力下降和脑病理积累有关。我们将采用联合治疗的方法，通过免疫治疗和行为富集来改善衰老犬模型的认知和减少神经病理学，这是一种可能直接转化为人类临床试验的方法。

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.