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、锻炼、认知增强和社会刺激与患阿尔茨海默病（AD）的风险和症状的严重程度有关。此外，在阿尔茨海默病的临床研究和转基因小鼠模型研究中，这些因素也经常被证明可以改善症状的各个方面。然而，标准的啮齿动物环境丰富范式并不适合于分离潜在的治疗方面，但一种为小鼠提供渐进式挑战、持续和认知特异性训练方案的方法将能够专门研究认知挑战（以下称为渐进式认知刺激或PCS）。目前尚不清楚这种持续复杂的认知挑战如何影响特定的大脑淀粉样蛋白病理、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方法——家庭笼环境富集（EE）进行比较，可能会非常揭示特定任务（PCS）与一般环境复杂性（EE）的相对影响。因此，我们的假设是：1)PCS可能改善大脑病理，并保持空间学习和记忆的表现；2)PCS和经典的情感表达方法通过作用于病理的多个方面而相互作用。为了验证这些假设，将首先确定PCS是否减少了转基因Tg-5xFAD小鼠的大脑淀粉样蛋白相关病理并保留了空间学习和记忆能力。接下来，将确定PCS与家庭笼式EE的比较，以确定是否需要这些方法的组合来实现最大的效益，以及它们是否对病理有不同的影响。我们将采用一种特性良好的转基因小鼠模型来研究大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差异贡献。所建立的Tg-5xFAD小鼠是早发性和强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发展为行为障碍。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，提供保护淀粉样蛋白病理和保持新的学习空间任务？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.