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

识别关键运动组织中的弹性蛋白，这些蛋白会导致运动和认知能力下降，并抵消大脑内外 ADRD 病理的负面影响

• 批准号: 10369971
• 负责人: ARON S BUCHMAN
• 金额: $ 135.45万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369971
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; American; Area; Attention; Behavior; Biological Markers; Brain; Brain Stem; Brain region; Cognitive; Complement; Data; Dementia; Dorsal; Drug Targeting; Elderly; Exhibits; Gene Proteins; Genes; Horns; Impaired cognition; Individual Differences; Lateral; Lead; Link; Loneliness; Measures; Memory; Monitor; Motor; Motor Neurons; Movement; Muscle; Nerve; Pathology; Persons; Pharmaceutical Preparations; Prefrontal Cortex; Proteins; Proteomics; Public Health; Publishing; Reaction; Resources; Risk Factors; Sampling; Specificity; Spinal; Spinal Cord; System; Systems Biology; Testing; Time; Tissues; Validation; Volition; Work; cognitive ability; cognitive function; disability; disease phenotype; drug discovery; gene discovery; indexing; link protein; loss of function; modifiable risk; novel; pre-clinical; prevent; quadriceps muscle; relating to nervous system; resilience; social; transcriptome; transcriptome sequencing

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.

运动是一种与阿尔茨海默病和相关痴呆症 (ADRD) 相关的意志行为。尽管许多老年人表现出一定程度的阿尔茨海默病和相关病症，但这些病症降低运动能力的程度各不相同。相同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衰退和另一个成年人的轻微损失有关。在患有阿尔茨海默病和相关病症的情况下保持运动或衰退速度较慢的成年人表现出运动弹性。为了提高运动恢复能力，识别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。共享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相关并不奇怪。这项研究将补充我们利用“认知”大脑区域的深层组学和关键“运动区域”的深层组学不断发现的弹性，以识别可能提供运动和认知弹性的新基因和蛋白质。 本研究响应 NOT-AG-20-053。我们选择了 3 个关键的运动组织来鉴定运动弹性蛋白，这些蛋白可能抵消阿尔茨海默病和相关痴呆 (ADRD) 病理学以及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) 脑干和脊髓的阿尔茨海默病病理学与痴呆的较高几率相关。 2）脊髓运动神经元、神经和肌肉的变性存在较大的个体差异，突出需要测量它们的变性以隔离运动弹性。 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，在之前的工作中识别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，因为高质量的 RNAseq 数据（概括为共表达模块）是从来自相同死者的 3 个关键运动组织（大脑 [SMA]、脊髓和肌肉）获得的。 5）正如假设的那样，在分离出运动弹性后，我们发现了 DLPFC 中为运动或认知衰退提供弹性的蛋白质，以及一些为两者提供弹性的蛋白质。 运动恢复力表现为运动衰退较慢。我们将量化阿尔茨海默氏病和大脑、脑干、脊髓、神经和肌肉中的相关病理，以分离运动恢复能力，即阿尔茨海默病和相关病理和退化无法解释的运动衰退。目标 1 将应用系统生物学方法来分析 3 个关键运动组织（大脑、脊髓和肌肉）的转录组数据，以发现可能提供运动弹性的基因。目标 2 将使用 SRM 蛋白验证这些基因，并在独立的成人样本中验证这些蛋白与运动能力下降有关。目标 3 将测试运动弹性蛋白是否也提供认知弹性，以及将多种蛋白质聚合到特定于人的指数中是否可以量化与阿尔茨海默病表型相关的高和低弹性。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。尽管存在无法治疗的阿尔茨海默病和相关病理，但弹性蛋白是维持运动和认知功能的药物发现的高价值目标。这些数据还将揭示运动和认知能力下降的机制以及提供弹性的风险因素。