Beta-Amyloid Immunization in a Canine Model of Aging

描述(申请人提供)：阿尔茨海默病(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-淀粉样多肽(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，可以减少AD患者大脑中A？的产生、沉积或增强其清除。在阿尔茨海默病转基因小鼠模型中，纤维蛋白A？1-42免疫后可防止或减少A？的沉积。此外，无论是主动免疫还是被动免疫，抗A抗体都能改善学习和记忆。在转基因小鼠工作的基础上，一项临床试验(AN1792)在服用纤维蛋白A？42的AD患者中启动。这项研究报告了认知方面的好处，尸检研究表明大脑A？减少了。我们将免疫疗法的研究扩展到人类大脑老化的犬类模型中，这种模型会自然地发展为人类A型血症和认知能力下降。老年动物主动免疫2年以上(共25次注射)。我们在免疫的老年比格犬身上的结果显示，脑A降低，执行功能改善。我们假设我们可以在更大程度上改善认知，并通过结合治疗和干预将认知改善扩展到包括多个领域，这可能会在移除A？后恢复神经元健康。因此，我们建议将免疫治疗与老年犬的行为丰富结合起来，并针对两种可能汇合的分子途径提供额外的好处。我们预测，当我们将免疫治疗与行为丰富相结合时，老年狗将表现出显著的认知改善、认知维持和神经病理减轻。此外，联合治疗将比单独治疗对认知和神经病理提供更大的好处。狗提供了一个独特的模型系统，在这个系统中开发组合治疗方法，包括减少AD病理和改善认知的免疫疗法，这些方法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堆积有关。我们将使用一种联合治疗的方法，通过免疫治疗和行为丰富来改善犬衰老模型的认知和减少神经病理，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.