Beta-Amyloid Immunization in a Canine Model of Aging

阿尔茨海默病(AD)与进行性认知功能减退和老年性脑积聚有关 斑块和神经原纤维缠结。老年斑含有β-淀粉样肽(A？)，它被认为是 在这种疾病中起到致病作用。因此，许多治疗方法正在开发中，可能会减少 在AD患者脑组织中产生、沉积或增强A？的清除。在转基因小鼠中 在阿尔茨海默病模型中，纤维蛋白A免疫后可防止或减少A？的沉积。此外， 学习和记忆可以通过主动或被动的抗A抗体免疫来改善。论 在转基因小鼠的工作基础上，在AD患者中开始了一项临床试验(AN1792) 原纤维A？42。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自然发育的人脑老化的犬模型中。 人类A型血与认知功能衰退。老年动物被积极免疫超过2年(25次注射 总计)。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，并将认知改善扩展到 包括多个域，通过结合治疗和干预可以在A？之后恢复神经元健康 移走。因此，我们建议将免疫治疗与老年犬和靶点的行为丰富相结合。 两条分子途径可能会聚在一起提供额外的好处。我们预测上了年纪的狗会出现 当我们结合时，显著的认知改善，认知的维持和神经病理的减少 行为浓缩的免疫疗法。此外，联合治疗将为以下患者提供更大的好处 认知和神经病理都比单独治疗要好。犬科动物提供了一个独特的模型系统 开发包括免疫疗法在内的联合治疗方法，以减少AD的病理和 改善认知，这可能会更直接地转化为人类临床试验。

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.