Systems Genetic Analysis of Cognitive Resilience Using Multi-Parent Crosses

项目摘要/摘要 认知韧性是一种个体对衰老最具破坏性的影响具有抵抗力的现象 认知方面--长寿但仍保持正常认知功能的人(如百岁老人) 根据概念定义，据说表现出较高的认知储备或韧性(参见储备 和Resilience NIA Consortium)。因此，促进认知储备和韧性的遗传因素可能会提供 治疗和预防各种年龄相关性痴呆认知功能衰退的主要目标 包括阿尔茨海默病(AD)和阿尔茨海默病相关痴呆(ADRD)。我们的总体目标 是通过使用网络方法整合数据来确定认知储备和弹性的驱动因素 收集自多样性杂交(DO)小鼠模型和人类数据。作为父级的一部分生成的数据 该研究表明，细胞类型组成的区域性变化可能是导致 确定认知储备和复原力的个体差异。全脑空间研究的最新进展 分析大脑储备和恢复能力的相关性，特别是高通量平台的出现 为了进行大规模免疫组织化学(IHC)标记数百只小鼠大脑中的多种细胞类型， 现在使评估认知储备和韧性的区域和细胞类型特定特征成为可能 用于评估认知、运动、睡眠和代谢的相同小鼠的临床相关特征 症状，这是对我们正在进行的工作的有力补充，并增加了新的信息层 关于我们的多尺度网络模型的区域和细胞类型的特殊性。有了拟议的补编， 我们将能够识别与认知储备相关的特定大脑区域和细胞类型的变化 以及它们与阿尔茨海默病和老年性痴呆过渡的关系。这个项目将 提供新颖的脑区和细胞类型，促进健康的大脑衰老(储备)和抗衰老能力。 在此之前，我们将对这些数据进行注释、整理并迅速向广大科学界传播 出版，以最大限度地利用这些数据进行荟萃分析和系统生物学研究。

PROJECT SUMMARY/ABSTRACT Cognitive resilience is a phenomenon whereby individuals are resistant to the most damaging effects of aging on cognition – individuals that maintain normal cognitive function despite being long-lived (e.g. centenarians) are said to exhibit high cognitive reserve or resilience depending on the conceptual definitions (see Reserve and Resilience NIA Consortium). Genetic factors promoting cognitive reserve and resilience may thus provide key targets for treatment and prevention of cognitive decline across a spectrum of age-related dementias including Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). Our overall objective is to identify drivers of cognitive reserve and resilience by using network approaches to integrate data collected from Diversity Outbred (DO) mouse models with human data. Data generated as part of the parent award indicates that regional changes in cell-type composition may be a significant contributing factor in determining individual differences in cognitive reserve and resilience. Recent advances in brain-wide spatial analyses of correlates of brain reserve and resilience, and particularly the advent of high throughput platforms for large-scale immunohistochemistry (IHC) to label multiple cell types throughout hundreds of mouse brains, now make it feasible to assess region and cell type specific hallmarks of cognitive reserve and resilience and clinically relevant traits in the same mice as used for assessing cognition, motor, sleep, and metabolic symptoms, representing a powerful complement to our ongoing work and adding a new layer of information regarding regional and cell-type specificity to our multi-scale network model. With the proposed supplement, we will be able to identify changes in specific brain regions and cell types associated with cognitive reserve and their relationship to transition towards Alzheimer’s disease and age-related dementias. This project will deliver novel brain regions and cell types for promoting healthy brain aging (reserve) and resilience to aging. We will annotate, curate, and rapidly disseminate the data to the broad scientific community prior to publication to maximize the usability of these data for meta-analysis and systems biology research.