A Murine Progressive Cognitive Stimulation (PCS) Model to Ameliorate Alzheimer s

描述（由申请人提供）：生活方式因素，如饮食，运动，认知丰富和社会刺激与获得阿尔茨海默病（AD）的风险和症状的严重程度有关。此外，在临床研究和AD转基因小鼠模型的研究中，这些因素也经常被证明可以改善症状。然而，标准啮齿动物环境富集范例不太适合于区分潜在的治疗方面，但是用于向小鼠提供渐进挑战性的、持续的和认知特异性的训练方案的方法将能够特异性地研究认知挑战（下文称为渐进认知刺激或PCS）。目前尚不清楚这种持续的复杂认知挑战如何影响特定的大脑淀粉样蛋白病理学，相关的神经炎症和新学习潜力的表现。此外，如何将这种复杂的认知挑战与经典的方法，家庭笼环境富集（EE）相比，可能非常揭示特定任务（PCS）与一般环境复杂性（EE）的相对影响。因此，我们的建议的假设是1）PCS可以改善大脑病理和保护空间学习和记忆性能，和2）PCS和经典的EE方法将通过作用于病理的多个方面而相互作用。为了测试这些假设，首先确定PCS是否减少转基因Tg-5xFAD小鼠中的脑淀粉样蛋白相关病理并保留空间学习和记忆能力。接下来，将确定PCS与饲养笼EE的比较情况，以确定是否需要这些方法的组合来实现最大获益，以及它们是否对病理学有不同的影响。将采用充分表征的转基因小鼠模型来研究脑微血管淀粉样蛋白和脑实质淀粉样蛋白对标准和复杂学习和记忆任务损伤的不同贡献。建立的Tg-5xFAD小鼠是早发性和稳健的实质淀粉样蛋白积累的模型。Tg-5xFAD小鼠表现出斑块相关的神经炎症并出现行为障碍。这些研究旨在解决重要和及时的问题，包括：长期的认知特异性刺激，通过PCS，提供保护淀粉样病变和保存新的学习空间任务？这些研究的完成将为不同的认知干预如何影响淀粉样蛋白病理提供有价值的见解。

DESCRIPTION (provided by applicant): Lifestyle factors, such as diet, exercise, cognitive enrichment, and social stimulation are related to the risk of acquiring Alzheimer's disease (AD) and the severity of the symptoms. Furthermore, in both clinical studies and in studies in transgenic mouse models of AD, these factors have also often been shown to improve aspects of the symptoms. However, standard rodent environmental enrichment paradigms are not well suited for teasing apart the potential therapeutic aspects, but a method for providing a progressively challenging, sustained and cognitive-specific training regimen to mice would be able to study the cognitive challenge specifically (hereafter referred to as Progressive Cognitive Stimulation or PCS). It is unknown how such a sustained complex cognitive challenge might impact specific cerebral amyloid pathologies, associated neuroinflammation, and performance on the potential for new learning. Furthermore, how this complex cognitive challenge compares to a classic methodology, home-cage environmental enrichment (EE), is likely to be very revealing of the relative impacts of task-specific (PCS) versus general environmental complexity (EE). Accordingly, the hypotheses of our proposal are 1) PCS may ameliorate cerebral pathologies and preserve spatial learning and memory performance, and 2) PCS and the classic EE approach will interact by acting on multiple aspects of pathology. To test these hypotheses, it will first be determined if PCS reduces cerebral amyloid associated pathologies and preserves spatial learning and memory ability in transgenic Tg-5xFAD mice. Next, it will be determined how PCS compares to home-cage EE to determine whether a combination of these methodologies is required to achieve maximal benefits and whether they have different impacts on pathology. A well-characterized transgenic mouse model will be employed to investigate the differential contributions of cerebral microvascular amyloid and parenchymal amyloid to impairments of standard and complex learning and memory tasks. The established Tg-5xFAD mouse is a model of early-onset and robust parenchymal amyloid accumulation. Tg-5xFAD mice exhibit plaque-associated neuroinflammation and develop behavioral impairments. These studies intend to address important and timely questions including: Does long term cognitive-specific stimulation, through PCS, provide protection from amyloid pathologies and preserve new learning of spatial tasks? Completion of these studies will provide valuable insight into how different cognitive interventions impact on amyloid pathologies.