Beta-Amyloid Immunization in a Canine Model of Aging

阿尔茨海默病（AD）与进行性认知衰退和老年性痴呆的积累有关。 斑块和神经纤维缠结。老年斑含有β-淀粉样肽（A），它被认为是 在疾病中起着致病作用。因此，正在开发许多治疗剂，其可以减少 产生、沉积或增强AD患者脑中A？的清除。转基因小鼠 在AD模型中，用纤维状A <$1 - 42免疫后可以预防或减少A <$的沉积。此外，本发明还 学习和记忆通过主动或被动免疫接种抗A？抗体而得到改善。上 在转基因小鼠工作的基础上，在AD患者中开始了临床试验（AN 1792）， 42.第四十二章在这项研究中报告了认知益处，尸检研究显示大脑A？减少。 我们将免疫治疗研究扩展到人类大脑老化的犬模型中， 人类A型和认知能力下降将老龄动物主动免疫超过2年（25次注射， 共计）。我们在免疫老年比格犬中的结果显示，大脑A？减少，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 包括多个领域，通过联合治疗与干预，可以恢复神经元健康后， 的拔除.因此，我们建议将联合收割机免疫治疗与行为富集相结合， 这两种分子途径可能会汇聚在一起，提供额外的好处。我们预测年老的狗 当我们将联合收割机与其他治疗方法结合使用时， 免疫疗法与行为富集。此外，联合治疗将为患者提供更大的益处。 认知和神经病理学方面的作用。犬提供了一个独特的模型系统， 该计划旨在开发涉及免疫疗法的组合治疗方法，以减少AD病理， 改善认知，这可能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.