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

运动是一种意志行为，与阿尔茨海默病和相关痴呆症(ADRD)有关。虽然许多老年人表现出一定程度的阿尔茨海默氏症和相关的病理，但这些病理损害运动的程度各不相同。等量的阿尔茨海默氏症和相关的病理可能与一个成年人的迅速衰退和另一个成年人的轻微衰退有关。在阿尔茨海默病和相关的病理情况下，保持运动或下降速度较慢的成年人表现出运动韧性。为了促进运动韧性，关键是要确定能够抵消阿尔茨海默病和相关病理的负面影响的危险因素或蛋白质。共享的神经底物是控制运动的运动和认知资源的基础。因此，认知韧性蛋白与运动韧性相关也就不足为奇了。这项研究将补充我们正在进行的弹性发现，使用“认知”大脑区域的深层组学和关键“运动区”的深层组学，以确定可能提供运动和认知弹性的新基因和蛋白质。 这项研究回应了NOT-AG-20-053。我们选择了3个关键的运动组织，在其中识别运动弹性蛋白，这些蛋白质可能抵消阿尔茨海默病和相关痴呆(ADRD)和运动系统退化的病理影响。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与患痴呆症的几率更高有关。2)脊髓运动神经元、神经和肌肉变性的个体差异很大，突出了测量它们的变性以分离运动弹性的必要性。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质(DLPFC)的RNAseq，在以前的工作中发现了认知弹性基因和蛋白质。4)这种方法可以在运动组织中获得成功，因为高质量的RNAseq数据总结为共表达模块，从同一死者的3个关键运动组织(脑[SMA]、脊髓和肌肉)获得。5)如假设的那样，在分离出运动弹性后，我们在DLPFC中发现了为运动或认知衰退提供弹性的蛋白质，以及一些为两者都提供弹性的蛋白质。 运动复原力表现为运动下降较慢。我们将量化阿尔茨海默病和相关的大脑、脑干、脊髓、神经和肌肉的病理，以分离运动韧性，即阿尔茨海默病和相关的病理和退行性疾病无法解释的运动下降。目标1将应用系统生物学方法转录3个关键运动组织(脑、脊髓和肌肉)的基因组数据，以发现可能提供运动弹性的基因。AIM 2将用SRM蛋白验证这些基因，并在一个独立的成人样本中验证这些蛋白与运动性衰退有关。AIM 3将测试运动弹性蛋白是否也提供认知弹性，以及是否将多个蛋白质聚合到一个特定于人的指数中来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风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靶点，可维持运动和认知功能，尽管存在无法治疗的阿尔茨海默病和相关病理。这些数据还将提供有关运动和认知衰退的潜在机制以及提供弹性的风险因素的信息。

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.