Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain

运动是一种与阿尔茨海默病和相关痴呆（ADRD）有关的意志行为。虽然许多老年人表现出一定程度的阿尔茨海默病和相关的病理，这些病理降低运动的程度各不相同。同样数量的阿尔茨海默病和相关病理可能与一个成年人的快速下降和另一个成年人的轻微损失有关。一个成年人谁保持运动或有一个较慢的速度下降，在阿尔茨海默氏病和相关的病理表现出运动弹性。为了促进运动恢复力，确定抵消阿尔茨海默病和相关病理的负面影响的风险因素或蛋白质至关重要。共同的神经基质是控制运动的运动和认知资源的基础。因此，认知弹性蛋白与运动弹性有关也就不足为奇了。这项研究将补充我们正在进行的韧性发现，使用深度组学在“认知”大脑区域与深度组学在关键的“运动区域”，以确定可能提供运动和认知韧性的新基因和蛋白质。 本研究响应NOT-AG-20-053。我们选择了3个关键的运动组织，以确定运动弹性蛋白，这些蛋白可能抵消阿尔茨海默病和相关痴呆症（ADRD）的病理学和运动系统退化的负面影响。然后，我们将测试其中一些蛋白质是否也提供认知弹性。 令人信服的数据支持这项研究：1）脑干和脊髓中的阿尔茨海默病病理学与痴呆症的更高几率有关。2)脊髓运动神经元、神经和肌肉退化的巨大个体差异突出了测量其退化以分离运动恢复力的必要性。3)我们的系统生物学和蛋白质验证方法应用于背外侧前额叶皮层（DLPFC）的RNAseq，在先前的工作中鉴定了认知弹性基因和蛋白质。4)这种方法可以在运动组织中取得成功，因为从来自相同死者的3个关键运动组织（脑[SMA]、脊髓和肌肉）获得了高质量的RNAseq数据（总结为共表达模块）。5)正如假设的那样，在分离运动恢复力后，我们确定了DLPFC中为运动或认知下降提供恢复力的蛋白质，以及一些为两者提供恢复力的蛋白质。 运动恢复力表现为较慢的运动衰退。我们将量化阿尔茨海默病和脑、脑干、脊髓、神经和肌肉中的相关病理，以分离运动恢复力，即，不能用阿尔茨海默病和相关病理学和变性解释的运动衰退。目标1将应用系统生物学方法从3个关键运动组织（大脑，脊髓和肌肉）的转录组数据中发现可能提供运动恢复力的基因。目的2将验证这些基因与SRM蛋白，并验证这些蛋白质与运动功能下降在一个独立的成年人样本。目标3将测试运动弹性蛋白是否也提供认知弹性，以及将多种蛋白聚集成一个人特异性指数是否量化与阿尔茨海默病表型相关的高弹性和低弹性。目标4将测试弹性蛋白是否将危险因素与运动和认知能力下降联系起来。弹性蛋白是药物发现的高价值目标，以维持运动和认知功能，尽管存在不可治疗的阿尔茨海默病和相关病理。这些数据还将为运动和认知能力下降的潜在机制以及提供弹性的风险因素提供信息。

Movement is a volitional behavior linked to Alzheimer’s disease and related dementias (ADRD). Though many older adults show some degree of Alzheimer’s disease and related pathologies, the extent that these pathologies degrade movement varies. The same amount of Alzheimer’s disease and related pathologies may be related to rapid decline in one adult and little loss in another. An adult who maintains movement or has a slower rate of decline in the presence of Alzheimer’s disease and related pathologies manifests motor resilience. To promote motor resilience, it is crucial to identify risk factors or proteins that offset the negative effects of Alzheimer’s disease and related pathologies. Shared neural substrate underlies motor and cognitive resources that control movement. So, it’s not surprising that cognitive resilience proteins are related to motor resilience. This study will complement our ongoing discovery of resilience using deep omics in “cognitive” brain regions with deep omics in key “motor regions” to identify new genes and proteins that may provide motor and cognitive resilience. This study responds to NOT-AG-20-053. We selected 3 key motor tissues in which to identify motor resilience proteins that may offset the negative effects of pathologies of Alzheimer’s disease and related dementias (ADRD) and degeneration in motor systems. We will then test if some of these proteins also provide cognitive resilience. Compelling data support this study: 1) Alzheimer’s disease pathology in brainstem and spinal cord is related to a higher odds of dementia. 2) Large individual differences in degeneration of spinal motoneurons, nerve and muscle, highlight the need to measure their degeneration to isolate motor resilience. 3) Our systems biology and protein validation approach applied to RNAseq in dorsal lateral prefrontal cortex (DLPFC) identified cognitive resilience genes and proteins in prior work. 4) This approach can succeed in motor tissues as high quality RNAseq data, summarized as co-expression modules, was obtained from 3 key motor tissues (brain [SMA], spinal cord and muscle) from the same decedents. 5) As hypothesized, after isolating motor resilience, we identified proteins in DLPFC that provide resilience for motor or cognitive decline and some that provide resilience for both. Motor resilience manifests as slower motor decline. We will quantify Alzheimer’s disease and related pathologies in brain, brainstem, spinal cord, nerve and muscle to isolate motor resilience i.e., motor decline not explained by Alzheimer’s disease and related pathologies and degeneration. Aim 1 will apply a systems biology approach to transcriptome data from 3 key motor tissues (brain, spinal cord and muscle) to discover genes that may provide motor resilience. Aim 2 will verify these genes with SRM proteins and validate that these proteins are related to motor decline in an independent sample of adults. Aim 3 will test if motor resilience proteins also provide cognitive resilience and if aggregating multiple proteins into a person-specific index quantifies high and low resilience related to Alzheimer’s disease phenotypes. Aim 4 will test if resilience proteins link risk factors with motor and cognitive decline. Resilience proteins are high value targets for drug discovery to maintain motor and cognitive function despite the presence of untreatable Alzheimer’s disease and related pathologies. These data will also inform on mechanisms underlying motor and cognitive decline and risk factors which provide resilience.