Accelerated Sarcopenia in Early Alzheimer's Disease

总结： 越来越多的证据表明，AD患者的身体功能早在认知功能下降之前就逐渐下降。 症状证明了痴呆症的临床诊断。这些早期的变化通常发生在促进 协调运动功能位于整个中枢神经系统，它们通过外周 神经通路进入肌肉骨骼结构。阐明这些运动机制可能指向 有效的AD干预措施。 在AD中，瘦肌肉质量的损失先于脑萎缩和认知障碍数年。AD 患者表现出减少的体力活动，这表明相关的行为变化可能会导致丧失 瘦体重然而，即使在控制了身体活动水平之后， 因此，在AD中观察到的身体活动的下降并不能完全解释大脑体积的加速损失。 早期AD的肌肉质量和强度（肌肉减少症）。我们认为脑干交感神经系统的损伤 神经元（SN），调节认知和骨骼肌功能，首先导致肌肉减少症，然后认知 损伤 我们提出，投射到脊髓中间外侧的脑桥去甲肾上腺素能神经元（A5）的一个亚群 神经节前肌柱（IML），并通过它们到达节后SN和后肢肌肉（交感神经 神经元投射到后肢肌肉，SNPHLM），调节运动神经元功能，神经肌肉接头 (NMJ)传输和骨骼肌神经支配、质量和强度。剩下的A5神经元突触 与几个目标，包括蓝斑（LC）神经元（A6），这是必不可少的维持 认知功能，但不是与NMJ。对于AD，A5 SNPHLM变得对累积损伤敏感， 导致了早期运动障碍光遗传学、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。 本课题的主要目的是：（1）明确A5 SNPHLM在肌肉运动神经失神经支配、NMJ损伤中的作用 传输，减少去甲肾上腺素（NE）释放在NMJ，并减少肾上腺素受体GPCR- 在AD的早期、中期和晚期阶段介导的信号传导;和（2）为了确定是否化学发生学 在AD的不同阶段调节A5 SNPHLM增强骨骼肌交感神经和运动神经 神经支配和延迟或逆转加速的肌肉减少症。 本项目将明确中枢自主神经元在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神经中枢调节器将使 痴呆前期AD的检测和针对每个疾病阶段的有效治疗的制定。

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.