Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders

摘要 对PAR 17-029的反应：在脑梗死患者中系统或非神经系统与大脑之间的动态相互作用 在衰老和AD中，这项研究将确定导致活动能力受损的分子机制，这是一个未充分研究的问题 老龄化和AD表型，如NIA研讨会所强调的，老龄化，中枢神经系统和流动性。AD和其他脑 病理学与老年痴呆和非痴呆患者的活动能力受损有关，但不能完全解释 行动不便。这些病理从大脑延伸到脊髓，但即使考虑到这些 病理学不能完全解释流动性，并且这些病理学的分子驱动因素是未知的。这 这表明，在这些组织中也存在未被识别的没有病理足迹的驱动器。 移动性来自于从大脑延伸到脊髓和肌肉的相互作用的子系统。 因此，这项对老年人的死后研究将确定分子驱动因素（基因及其 在控制AD和其他CNS存在的关键活动性组织中， 病理学这项研究将利用临床和尸检资源，从老年参与者的拉什 记忆和老化项目（R 01 AG 17917）。我们的系统生物学方法将应用于新的基因 从脑、脊髓和肌肉中的关键移动性组织获得的表达数据（Aim 1）。纸巾会来的 来自相同的人，所有这些人都在接近死亡的时候用可穿戴传感器进行了步态测试。 在每种组织中，我们将确定控制CNS病理的迁移率相关分子系统（Aim 2）。 因果网络推理将被用来提名有影响力的基因控制这些系统（Aim 3）。 验证这些组织内和跨这些组织的影响基因的蛋白质水平将产生一个高置信度的 基因驱动受损的流动性（Aim 4）。令人信服的试点研究支持这一建议。1)的组合 可穿戴传感器的移动性指标比传统的步态速度对AD痴呆更具体。2)AD和 其他病理延伸到脊髓，并与流动性有关，强调需要确定驱动因素， 大脑外的运动组织中的这些病理。3)此外，CNS病理的解释力有限， 强调需要确定关键运动组织中运动障碍的分子驱动因素， 没有已知的病理痕迹4)高质量的全基因组转录组数据提取的关键 运动组织中差异表达的基因与步态、认知和AD病理有关。5)应用 将系统生物学方法应用于大脑皮层认知基因网络，然后用蛋白质进行验证， 确定了驱动认知的皮质蛋白。利用广泛的专业知识，这项研究将提供深入的 描述内部和外部相互连接的子系统内的分子驱动器 CNS。验证有影响力的基因提供了一种方法，通过提供新的 治疗目标这项研究有可能对老龄化研究产生持续的影响， 保持健康并减少衰老和AD的主要不良健康后果。

ABSTRACT Responding to PAR 17-029: Dynamic Interactions between systemic or non-neuronal systems and the brain in aging and in AD, this study will identify the molecular mechanisms driving impaired mobility, an understudied aging and AD phenotype, as highlighted by NIA workshops, Aging, the CNS, and Mobility. AD and other brain pathologies are related to impaired mobility in older adults with and without dementia, but do not fully explain impaired mobility. These pathologies extend beyond the brain to spinal cord, but even accounting for these pathologies does not fully explain mobility and the molecular drivers of these pathologies are unknown. This suggests that there are also drivers without a pathologic footprint that remain unidentified in these tissues. Mobility derives from interacting subsystems that extend beyond the brain to spinal cord and muscle. Therefore, this postmortem study in older adults will identify molecular drivers (genes and their proteins) of impaired mobility in key mobility tissues controlling for the presence of AD and other CNS pathologies. This study will leverage clinical and postmortem resources from older participants of the Rush Memory and Aging Project (R01AG17917). Our systems biology approach will be applied to new gene expression data obtained from key mobility tissues in brain, spinal cord and muscle (Aim1). Tissues will come from the same persons, all of whom had instrumented gait testing with a wearable sensor proximate to death. In each tissue, we will identify mobility-related molecular systems controlling for CNS pathologies (Aim2). Causal network inference will be used to nominate influential genes controlling these systems (Aim3). Validating protein levels of influential genes within and across these tissues will yield a high-confidence list of genes driving impaired mobility (Aim4). Compelling pilot studies support this proposal. 1) Combinations of wearable sensor mobility metrics are more specific for AD dementia than conventional gait speed. 2) AD and other pathologies extend to spinal cord and are related to mobility, emphasizing the need to identify drivers of these pathologies in motor tissues outside the brain. 3) Also, the limited explanatory power of CNS pathologies for mobility highlights the need to identify molecular drivers of impaired mobility in key motor tissues that may not have a known pathologic footprint. 4) High quality genome-wide transcriptomic data extracted from key motor tissues show differentially expressed genes are related to gait, cognition and AD pathology. 5) Applying the system biology methods to a cortical cognitive gene network, followed by validation with protein, we identified cortical proteins driving cognition. Leveraging broad expertise, this study will provide an in-depth description of the molecular drivers within interconnected subsystems underlying mobility within and outside the CNS. Validating influential genes provides a means to move beyond a descriptive study by providing novel therapeutic targets. This study has potential to make a sustained impact on aging research, inform on efforts to maintain ambulation and reduce a major adverse health consequence of aging and AD.