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： 累积证据表明AD患者身体功能逐渐在认知之前逐渐下降 症状需要对痴呆症进行临床诊断。这些早期的变化通常在促进的地区发展 并协调运动功能。它们位于整个中枢神经系统中，通过外围延伸 神经途径进入肌肉骨骼结构。阐明这些电机机构可能指向 有效的广告干预措施。 在AD中，瘦肌肉质量的损失先于几年的脑萎缩和认知障碍。广告 患者显示体育锻炼减少，表明相关的行为改变可能导致 瘦质量。但是，即使在控制体育锻炼水平之后，瘦肉质量也独立关联 随着脑体积 肌肉质量和力量（肌肉减少症）。我们提出对脑干同情的损害 调节认知和骨骼肌功能的神经元（SNS）首先导致肌肉减少症 损害。 我们建议将脊髓中间外侧的pontine甲肾上腺素能神经元（A5） 柱（IML）前神经节，并通过它们到后gionic sn和后肢肌肉（同情 投射给后肢肌肉的神经元，SNPHLM），调节运动神经元功能，神经肌肉连接 （NMJ）传播和骨骼肌神经支配，质量和力量。其余的A5神经元突触 有几个靶标，包括位点凝固（LC）神经元（A6），这对于维持 认知功能，但没有NMJ。使用AD，A5 SNPHLM容易受到累积损害的影响， 哪些占早期运动缺陷。光遗传学，化学遗传学和病毒载体逆行神经元 标签提供了新的机会来定义A5 SNPHLM在AD肌肉病理学和功能中的作用。 该项目的目的是：（1）定义A5 SNPHLM在肌肉运动神经上的作用，NMJ受损 传播，降低了NMJ的去甲肾上腺素（NE）释放，并减少了肾上腺素的GPCR- AD的早期，中和晚期介导的信号传导； （2）确定是否化学发生 在各个AD阶段对A5 SNPHLM的调节增强了骨骼肌肉交感神经和运动 神经和延误或逆转加速的肌肉减少症。 该项目将定义中央自主神经元在AD肌肉减少症中的作用，并预测疾病 进展。分析骨骼肌结构和功能的自主中心调节剂 检测预期AD和每个疾病阶段有效治疗的表述。