Accelerated Sarcopenia in Early Alzheimer's Disease

早期阿尔茨海默病加速肌肉减少症

• 批准号: 10589353
• 负责人: Osvaldo Delbono
• 金额: $ 76.64万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589353
• 关键词: 3xTg-AD mouse; Acceleration; Adrenergic Receptor; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Attenuated; Behavioral; Brain Stem; Cells; Central Nervous System; Chronic; Cognition; Cognitive; Dementia; Denervation; Deposition; Detection; Disease; Disease Progression; Drug Modulation; Formulation; G-Protein-Coupled Receptors; Genetic; Genetic Vectors; Hindlimb; Hyperactivity; Impaired cognition; Impairment; Inflammation; Intervention; Label; Mass Spectrum Analysis; Measures; Mediating; Molecular; Motor; Motor Neurons; Muscle; Muscle function; Musculoskeletal structure; Myopathy; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neuromuscular Junction; Neurons; Norepinephrine; Pathology; Pathway interactions; Peripheral; Peripheral Nerves; Phenotype; Physical Function; Physical activity; Pontine structure; Predisposition; Proteomics; Receptor Activation; Recombinant adeno-associated virus (rAAV); Regulation; Resolution; Risk; Role; Signal Transduction; Skeletal Muscle; Spinal Cord; Subgroup; Synapses; Testing; Thinness; Time; Viral Vector; brain volume; cerebral atrophy; clinical diagnosis; cognitive function; delivery vehicle; design; designer receptors exclusively activated by designer drugs; effective therapy; hyperphosphorylated tau; innovation; light gated; locus ceruleus structure; mild cognitive impairment; motor deficit; muscle form; muscle strength; muscular structure; nerve supply; neuron loss; noradrenergic; novel; optogenetics; patch clamp; prevent; receptor-mediated signaling; retrograde transport; sarcopenia; senescence; sensor; tau Proteins; tau aggregation; tau-1; transcriptome sequencing; transcriptomics; transmission process; vector

Summary: Accumulating evidence indicates that AD patient physical function gradually declines long before cognitive symptoms warrant a clinical diagnosis of dementia. These early changes often develop in regions that promote and coordinate motor function. Located throughout the central nervous system, they extend via peripheral nerve pathways into musculoskeletal structures. Elucidating these motor mechanism(s) may point toward effective AD interventions. In AD, loss of lean muscle mass precedes brain atrophy and cognitive impairment by several years. AD patients show reduced physical activity, suggesting that associated behavioral changes may result in loss of lean mass. However, even after controlling for physical activity levels, lean mass is independently associated with brain volume, so the decline in physical activity observed in AD does not fully explain accelerated loss in muscle mass and strength (sarcopenia) in early AD. We propose that damage to brainstem sympathetic neurons (SNs), which regulates cognitive and skeletal muscle function, leads first to sarcopenia, then cognitive impairment. We propose that a subgroup of pontine noradrenergic neurons (A5) that project to spinal cord intermediolateral column (IML) preganglionic and, through them, to postganglionic SN and hindlimb muscles (Sympathetic Neurons Projecting to Hindlimb Muscles, SNPHLM), regulates motoneuron function, neuromuscular junction (NMJ) transmission, and skeletal muscle innervation, mass, and strength. The remaining A5 neurons synapse with several targets, including the locus coeruleus (LC) neurons (A6), which are essential to maintaining cognitive function,but not with the NMJ. With AD, A5 SNPHLM become susceptible to cumulative damage, which accounts for early motor deficits. Optogenetics, chemogenetics, and viral vector retrograde neuron labeling provide new opportunities to define the role of A5 SNPHLM in AD muscle pathology and function. The aims of this project are: (1) To define the role of A5 SNPHLM in muscle motor denervation, impaired NMJ transmission, decreased norepinephrine (NE) release at the NMJ, and diminished adrenoceptor GPCR- mediated signaling in the early, middle, and late stages of AD; and (2) To determine whether chemogenetic modulation of A5 SNPHLM at various stages of AD enhances skeletal muscle sympathetic and motor innervation and delays or reverses accelerated sarcopenia. This project will define the role of central autonomic neurons in AD sarcopenia and predict disease progression. Analysis of autonomic central regulators of skeletal muscle structure and function will enable detection of predementia AD and formulation of effective treatments for each disease stage.

摘要： 越来越多的证据表明，阿尔茨海默病患者的身体功能在认知之前很久就逐渐下降 症状需要临床诊断为痴呆症。这些早期的变化通常发生在促进 并协调运动功能。它们位于整个中枢神经系统，通过外周延伸 神经通路进入肌肉骨骼结构。阐明这些运动机制(S)可能指向 有效的AD干预。 在阿尔茨海默病中，瘦肉量的减少先于大脑萎缩和认知障碍几年。广告 患者表现出体力活动减少，这表明相关的行为变化可能导致 瘦身质量。然而，即使在控制了体力活动水平之后，瘦体重也是独立相关的 所以在AD中观察到的体力活动的下降并不能完全解释AD的加速损失 AD早期的肌肉质量和力量(骨量减少)。我们认为脑干交感神经受损 神经元(SNs)调节认知和骨骼肌功能，首先导致骨骼肌减少，然后是认知 减损。 我们认为，桥脑去甲肾上腺素能神经元(A5)的一个亚群投射到脊髓中间外侧。 柱(IML)节前，并通过它们到达节后SN和后肢肌肉(交感 投射到后肢肌肉的神经元，调节运动神经元功能，神经肌肉连接 (NMJ)传递，骨骼肌的神经支配、质量和力量。其余的A5神经元突触 有几个靶点，包括蓝斑(LC)神经元(A6)，它们是维持 认知功能，但与NMJ无关。对于AD，A5 SNPHLM变得容易累积损伤， 这就是早期运动缺陷的原因。光遗传学、化学遗传学和病毒载体逆行神经元 标记为确定A5 SNPHLM在AD肌肉病理和功能中的作用提供了新的机会。 本项目的目的是：(1)明确A5SNPHLM在肌肉运动失神经、受损的NMJ中的作用 传递，减少去甲肾上腺素(NE)在NMJ的释放，并减少肾上腺素受体GPCR. 介导AD早期、中期和晚期的信号转导；以及(2)确定化学发生是否 A5 SNPHLM在AD不同阶段的调节增强骨骼肌交感神经和运动 神经支配和延缓或逆转加速的石棺减少。 该项目将确定中枢自主神经在AD肉质减少症中的作用并预测疾病 进步。对骨骼肌结构和功能的自主中枢调节的分析将使 检测痴呆前期AD，并为每个疾病阶段制定有效的治疗方案。