Ameliorating Synaptic and Mitochondrial Dysfunctions of the Respiratory Neuromotor System in Alzheimer's Disease

改善阿尔茨海默病呼吸神经运动系统的突触和线粒体功能障碍

• 批准号: 10905152
• 负责人: Matthew Fogarty
• 金额: $ 53.21万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10905152
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Behavior; Brain Stem; Central Nervous System; Cessation of life; Chronic Disease; Data; Deglutition; Dendritic Spines; Denervation; Disease; Effector Cell; Elderly; Etiology; Excitatory Synapse; Experimental Designs; Fiber; Functional disorder; Generations; Genetic; Glutamates; Human; Image; Impairment; Incidence; Individual; Inflammaging; Inhibitory Synapse; Knowledge; Maintenance; Membrane; Mitochondria; Morbidity - disease rate; Motor; Motor Neurons; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Nerve Degeneration; Neuromuscular Junction; Obstructive Sleep Apnea; Oranges; Outcome; Oxidative Stress; Pneumonia; Population; Publishing; Rattus; Research; Respiration; Respiration Disorders; Respiratory Diaphragm; Respiratory Muscles; Respiratory Tract Infections; Riluzole; Risk; Risk Factors; Rodent; Severities; Skeletal Muscle; Spinal Cord; Symptoms; Synapses; System; Techniques; Testing; Therapeutic; Tongue; Transversalis; Work; age group; age related; age-related muscle loss; density; design; experience; functional disability; functional improvement; gamma-Aminobutyric Acid; genioglossus muscle; human old age (65+); improved; improved outcome; innovation; mitochondrial dysfunction; mortality; motor control; motor impairment; neural; neuromuscular system; neuron loss; novel; novel therapeutic intervention; oral motor; phenylmethylpyrazolone; preservation; pressure; recruit; resilience; respiratory; sarcopenia; synaptic function; tau Proteins; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Behavior; Brain Stem; Central Nervous System; Cessation of life; Chronic Disease; Data; Deglutition; Dendritic Spines; Denervation; Disease; Effector Cell; Elderly; Etiology; Excitatory Synapse; Experimental Designs; Fiber; Functional disorder; Generations; Genetic; Glutamates; Human; Image; Impairment; Incidence; Individual; Inflammaging; Inhibitory Synapse; Knowledge; Maintenance; Membrane; Mitochondria; Morbidity - disease rate; Motor; Motor Neurons; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Nerve Degeneration; Neuromuscular Junction; Obstructive Sleep Apnea; Oranges; Outcome; Oxidative Stress; Pneumonia; Population; Publishing; Rattus; Research; Respiration; Respiration Disorders; Respiratory Diaphragm; Respiratory Muscles; Respiratory Tract Infections; Riluzole; Risk; Risk Factors; Rodent; Severities; Skeletal Muscle; Spinal Cord; Symptoms; Synapses; System; Techniques; Testing; Therapeutic; Tongue; Transversalis; Work; age group; age related; age-related muscle loss; density; design; experience; functional disability; functional improvement; gamma-Aminobutyric Acid; genioglossus muscle; human old age (65+); improved; improved outcome; innovation; mitochondrial dysfunction; mortality; motor control; motor impairment; neural; neuromuscular system; neuron loss; novel; novel therapeutic intervention; oral motor; phenylmethylpyrazolone; preservation; pressure; recruit; resilience; respiratory; sarcopenia; synaptic function; tau Proteins

ABSTRACT The studies in the proposal are focused on the neuromotor system in Alzheimer’s disease (AD) and natural aging. Increased age is associated with muscle atrophy and weakness (sarcopenia) and is a significant predictor of chronic disease and mortality in the elderly. Aging is a major risk factor for conditions such as AD and obstructive sleep apnea (OSA). In the elderly population, pneumonia incidence is 3-times higher than in younger age groups, with AD further increasing the incidence and severity of airway infections. The incidence of airway infection in aging and age-associated disorders is undoubtedly related to sarcopenia of the diaphragm muscles (DIAm) and discoordination of airway protective manoeuvres, which involve both DIAm and an assortment of other respiratory-associated muscles including individual tongue muscles. This proposal leverages the extensive experience of the PI in both respiratory neuromotor systems and in neurodegeneration. Previously, we found that DIAm sarcopenia was related to a loss of larger phrenic motor neurons (MNs) and subsequent denervation, consistent with motor unit specific effects on maximum transdiaphragmatic pressure generation. Our preliminary observations in both intrinsic (longitudinal and transversalis muscles) and extrinsic (genioglossus) tongue muscles suggest that sarcopenia in tongue may also be due to denervation. Despite the cause of age-related MN loss being unknown, clues from neurodegenerative conditions that affect MNs suggest that synaptic loss and mitochondrial disfunctions contribute to MN death, with disproportionate effects on larger MNs. The major conceptual advancement in this proposal is to comprehensively evaluate the entire motor unit: hypoglossal and phrenic MNs – recruited to perform motor tasks; neuromuscular junctions – connecting neural impulse to the muscle; and tongue and DIAm – the effector cell. We hypothesize that in old age and AD, motor impairments and loss of larger MNs (denervation) of respiratory muscles is underpinned by MN and NMJ synapse loss and mitochondrial dysfunction (reduced volume density, fragmentation and activity). In addition, we will trial two approaches to ameliorate the contribution of synaptic loss (via riluzole) or mitochondrial dysfunction (via edaravone) to MN death in AD and aging. The proposed studies employ an array of innovative techniques, with assessments ranging from sub-cellular through to system level behavior in Fischer 344 rats and in an AD model (TgF344-AD) on the same genetic background. In Aim 1, we will assess excitatory and inhibitory synapse loss, dendritic and dendritic spine loss, and survival of hypoglossal and phrenic MNs. Additionally, we will evaluate denervation, sarcopenia and functional impairments in tongue and DIAm across aging and AD. In Aim 2, we will assess mitochondrial volume density (MVD) and fragmentation and function SDHmax in hypoglossal and phrenic MNs and in tongue and DIAm in aging and AD. In Aim 3, we will assess whether mitigating synaptic dysfunction (by riluzole) and/or mitochondrial dysfunction (by edaravone) improves outcomes in respiratory MNs and muscles in aging and AD.

抽象的 该提案中的研究集中在阿尔茨海默氏病（AD）和自然的神经运动系统上 老化。年龄增加与肌肉萎缩和无力（肌肉减少症）有关，是一个重要的预测因子 古老的慢性疾病和死亡率。衰老是AD和诸如AD等疾病的主要危险因素 阻塞性睡眠呼吸暂停（OSA）。在最古老的人口中，肺炎发病率比年轻人高3倍 年龄组，广告进一步增加了气道感染的事件和严重程度。气道事件 衰老和年龄相关疾病的感染无疑与diaphragm肌肉的肌肉减少症有关 （直径）和受气道受保护的动作的不和谐，涉及直径和各种 其他与呼吸道相关的肌肉，包括各个舌头肌肉。该提案利用了广泛的 PI在呼吸神经运动系统和神经变性中的经验。以前，我们发现 该直径肌肉减少症与较大的Phren型运动神经元（MN）和随后的神经膜的丧失有关， 与电动机单位对最大透射压力产生的特异性影响一致。我们的初步 内在的（纵向和横向肌肉）和外部（Geniogloss）舌头的观察 肌肉表明舌头上的肌肉减少症也可能是由于神经支配所致。 尽管造成与年龄相关的MN损失的原因未知，但神经退行性疾病的线索 影响MN表明合成损失和线粒体的失调会导致MN死亡，并有 对较大的MN的影响不成比例。该提议中的主要概念进步是 全面评估整个电机单元：降低和伪造的MN-招募以执行运动任务； 神经肌肉连接 - 将神经浸渍连接到肌肉；以及舌头和直径 - 效应细胞。 我们假设在老年和AD，运动障碍以及呼吸道较大MN（神经）的损失 MN和NMJ突触丧失和线粒体功能障碍（量降低，体积密度降低， 分裂和活动）。此外，我们将试用两种改善突触的贡献的方法 损失（通过riluzole）或线粒体功能障碍（通过Edaravone）到AD和衰老中的MN死亡。 拟议的研究员工一系列创新技术，评估范围从亚细胞 直到Fischer 344大鼠和AD模型（TGF344-AD）中的系统水平行为直至相同的遗传 背景。在AIM 1中，我们将评估兴奋性和抑制性突触丧失，树突状和树突状脊柱损失， 降低和伪造的MN的生存。此外，我们将评估神经支配，肌肉减少症和 在衰老和AD中，功能障碍和DIAM的功能障碍。在AIM 2中，我们将评估线粒体量 密度（MVD）以及降低和伪造的MN中的碎片和功能SDHMAX以及舌头和直径 在衰老和广告中。在AIM 3中，我们将评估是否减轻突触功能障碍（由Riluzole）和/或 线粒体功能障碍（通过Edaravone）改善了衰老和AD中呼吸道MN和肌肉的结局。