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的响应：全身性或非神经性系统与大脑之间的动态相互作用 衰老和阿尔茨海默病，这项研究将确定导致行动能力受损的分子机制，这是一个未被研究的 衰老和AD表型，如NIA研讨会、衰老、中枢神经系统和流动性所强调的。AD和其他大脑 病理学与患有和不患有痴呆症的老年人的行动能力受损有关，但并不能完全解释 行动不便。这些病变从大脑延伸到脊髓，但即使考虑到这些 病理并不能完全解释移动性，这些病理的分子驱动因素也是未知的。这 这表明，在这些组织中，也有一些没有病理足迹的司机仍然没有被识别出来。 移动性来自相互作用的子系统，这些子系统从大脑延伸到脊髓和肌肉。 因此，这项对老年人的尸检研究将确定分子驱动因素(基因和他们的 蛋白质)在控制AD和其他中枢神经系统的存在的关键活动组织中的流动性受损 病理学。这项研究将利用来自Rush的老年参与者的临床和尸检资源 记忆与衰老项目(R01AG17917)。我们的系统生物学方法将应用于新基因 从大脑、脊髓和肌肉的关键活动组织获得的表达数据(Aim1)。纸巾会来的 来自相同的人，所有人都用一个接近死亡的可穿戴传感器进行了步态测试。 在每个组织中，我们将识别控制中枢神经系统病理的流动性相关分子系统(AIM2)。 因果网络推理将被用来提名控制这些系统的有影响力的基因(Aim3)。 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度可信的列表 驱动行动能力受损的基因(Aim4)。令人信服的试点研究支持这一提议。1)组合 与传统的步态速度相比，可穿戴传感器的移动性指标对AD痴呆更具特异性。2)AD和 其他病变延伸到脊髓，并与活动有关，强调需要确定驱动因素 这些病变存在于大脑以外的运动组织中。3)此外，中枢神经系统病理的解释能力有限 强调需要确定关键运动组织中流动性受损的分子驱动因素，这些因素可能 没有已知的病理足迹。4)从KEY提取的高质量全基因组转录数据 运动组织显示差异表达的基因与步态、认知和AD病理有关。5)申请 用系统生物学的方法构建了一个皮质认知基因网络，然后用蛋白质进行了验证 确定了驱动认知的皮质蛋白质。利用广泛的专业知识，这项研究将提供深入的 描述内部和外部流动性基础的互联子系统内的分子驱动因素 中枢神经系统。验证有影响力的基因提供了一种超越描述性研究的手段，通过提供新的 治疗靶点。这项研究有可能对老龄化研究产生持续影响，为以下努力提供信息 保持步行，减少衰老和阿尔茨海默病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.