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

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 该提案中的研究重点是阿尔茨海默病（AD）和自然疗法中的神经运动系统。 老化。年龄增长与肌肉萎缩和无力（肌肉减少症）相关，是一个重要的预测因素 老年人的慢性病和死亡率。衰老是 AD 和 AD 等疾病的主要风险因素 阻塞性睡眠呼吸暂停（OSA）。老年人肺炎发病率是年轻人的3倍 AD 进一步增加了气道感染的发生率和严重程度。气道发生率 衰老和年龄相关疾病的感染无疑与膈肌肌少症有关 (DIAm) 和气道保护动作不协调，其中涉及 DIAm 和各种 其他与呼吸相关的肌肉，包括个体舌头肌肉。该提案利用了广泛的 PI 在呼吸神经运动系统和神经退行性疾病方面的经验。此前，我们发现 DIAm 肌少症与较大膈运动神经元 (MN) 的丧失和随后的去神经支配有关， 与运动单位对最大跨膈压力产生的特定影响一致。我们的初步 舌内肌（纵向肌和横肌）和舌外肌（颏舌肌）的观察 肌肉表明，舌头肌肉减少症也可能是由于去神经支配所致。 尽管与年龄相关的 MN 丧失的原因尚不清楚，但来自神经退行性疾病的线索表明 影响 MN 的研究表明，突触丢失和线粒体功能障碍会导致 MN 死亡， 对较大的 MN 的影响不成比例。该提案的主要概念进步是 全面评估整个运动单位：舌下神经节和膈肌神经节——被招募来执行运动任务； 神经肌肉接头——将神经冲动连接到肌肉；舌头和 DIAm——效应细胞。 我们假设，在老年和 AD 中，运动障碍和呼吸系统较大 MN 的丧失（去神经支配） 肌肉的基础是 MN 和 NMJ 突触损失和线粒体功能障碍（体积密度降低， 碎片化和活动）。此外，我们将尝试两种方法来改善突触的贡献 AD 和衰老中的 MN 丢失（通过利鲁唑）或线粒体功能障碍（通过依达拉奉）导致 MN 死亡。 拟议的研究采用了一系列创新技术，评估范围从亚细胞 Fischer 344 大鼠和 AD 模型 (TgF344-AD) 中相同基因的系统水平行为 背景。在目标 1 中，我们将评估兴奋性和抑制性突触损失、树突和树突棘损失， 以及舌下和膈 MN 的存活。此外，我们将评估去神经支配、肌肉减少症和 衰老和 AD 过程中舌头和 DIAm 的功能障碍。在目标 2 中，我们将评估线粒体体积 舌下和膈 MN 以及舌和 DIAm 中的密度 (MVD) 以及碎片和功能 SDHmax 在衰老和 AD 方面。在目标 3 中，我们将评估是否减轻突触功能障碍（通过利鲁唑）和/或 线粒体功能障碍（依达拉奉）可改善衰老和 AD 中呼吸微神经和肌肉的结果。