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: 10599328
• 负责人: ARON S BUCHMAN
• 金额: $ 147.09万
• 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/10599328
• 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; Genes; Horns; Impaired cognition; Individual Differences; Lateral; 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; Tissues; Validation; Vertebral column; Work; cognitive ability; cognitive function; decrease resilience; disability; disease phenotype; drug discovery; gene discovery; indexing; link protein; loss of function; modifiable risk; neural; novel; pre-clinical; prevent; quadriceps muscle; 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.

运动是与阿尔茨海默氏病和相关的痴呆症（ADRD）的屈光度行为在阿尔茨海默氏病和相关病理的存在下保持运动率较慢，表现出促进运动弹性的能力控制运动的资源。具有弹性。 这项研究对我们选择了3个关键的运动组织，以鉴定出可能抵消阿尔茨海默氏病和相关痴呆症（ADRD）的赛车蛋白的3个关键运动蛋白测试其中一些蛋白质是否还具有认知弹性。 引人注目的数据支持这项研究：1）脊柱运动神经元，神经和肌肉退化的大2个iD差异，突出显示其退化以隔离运动的弹性。先前工作中的蛋白质。弹性，我们确定了DLPFC中的蛋白质，这些蛋白质为运动或认知能力下降提供了弹性，有些为两者提供了弹性。 运动的弹性表现为较慢的运动量，我们将量化阿尔茨海默氏病和肌肉中的相关病理学，以隔离运动性疾病，即运动不足，而不是由阿尔茨海默氏病和相关的病理学和变性的apple apple a苹果apple a键数据解释。运动组织的含量为2成年人。提供弹性的危险因素。