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.

概括： 越来越多的证据表明，早在认知能力出现之前，AD患者的身体机能就逐渐下降 症状需要痴呆症的临床诊断。这些早期的变化往往发生在促进 和协调运动功能。它们位于整个中枢神经系统，通过周围神经系统延伸 进入肌肉骨骼结构的神经通路。阐明这些运动机制可能指向 有效的 AD 干预措施。 在 AD 中，瘦肌肉质量的丧失先于脑萎缩和认知障碍数年。广告 患者表现出体力活动减少，表明相关的行为改变可能导致丧失 瘦体重。然而，即使在控制了体力活动水平之后，去脂体重也独立相关。 与脑容量有关，因此 AD 中观察到的体力活动下降并不能完全解释脑容量的加速损失 AD 早期的肌肉质量和力量（肌肉减少症）。我们认为脑干交感神经损伤 调节认知和骨骼肌功能的神经元（SN）首先导致肌肉减少症，然后导致认知障碍 损害。 我们提出，桥脑去甲肾上腺素能神经元 (A5) 的一个亚群投射到脊髓中外侧 神经节前柱 (IML)，并通过它们到达节后 SN 和后肢肌肉（交感神经 投射到后肢肌肉的神经元 (SNPHLM)，调节运动神经元功能、神经肌肉接头 (NMJ) 传输、骨骼肌神经支配、质量和强度。剩余的 A5 神经元突触 具有多个目标，包括蓝斑 (LC) 神经元 (A6)，这对于维持 认知功能，但与 NMJ 无关。随着 AD，A5 SNPHLM 变得容易受到累积损坏， 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 标签为定义 A5 SNPHLM 在 AD 肌肉病理学和功能中的作用提供了新的机会。 该项目的目标是：(1) 定义 A5 SNPHLM 在肌肉运动去神经、NMJ 受损中的作用 传输、NMJ 处去甲肾上腺素 (NE) 释放减少以及肾上腺素受体 GPCR- 减少 AD 早期、中期和晚期的介导信号传导； (2) 确定是否是化学遗传学 AD 各个阶段 A5 SNPHLM 的调节可增强骨骼肌交感神经和运动能力 神经支配并延迟或逆转加速的肌肉减少症。 该项目将定义中枢自主神经元在 AD 肌少症中的作用并预测疾病 进展。对骨骼肌结构和功能的自主中枢调节器的分析将使 检测痴呆症前期并制定针对每个疾病阶段的有效治疗方法。