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

摘要 该提案中的研究重点是阿尔茨海默病(AD)和自然 衰老。年龄增长与肌肉萎缩和虚弱(肌萎缩症)有关，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)。在老年人口中，肺炎发病率是年轻人的3倍。 年龄组中，AD进一步增加了呼吸道感染的发生率和严重程度。呼吸道感染的发生率 衰老和年龄相关疾病的感染无疑与横隔肌的肌质疏松症有关。 (DIAM)和呼吸道保护性动作的不协调，这涉及DIAM和一系列 其他与呼吸相关的肌肉，包括个别舌肌。这项建议利用了广泛的 呼吸神经运动系统和神经退行性变的PI经验。此前，我们发现 Diam石棺减少与较大的膈运动神经元(MN)的丧失和随后的失神经有关， 与发动机单元对最大跨隔膜压力产生的特定影响一致。我们的预赛 内源性(纵向和横翼肌)和外源性(颧舌肌)舌的观察 肌肉表明，舌部的骨质疏松症也可能是由于失神经造成的。 尽管与年龄相关的MN丢失的原因尚不清楚，但来自神经退行性疾病的线索 影响MNS提示突触丢失和线粒体功能障碍导致MN死亡， 对较大的跨国公司产生不成比例的影响。这项建议在概念上的主要进展是 全面评估整个运动单位：舌下和膈下MN--被招募来执行运动任务； 神经肌肉连接-连接神经冲动和肌肉；舌头和DIAM-效应细胞。 我们假设，在老年和阿尔茨海默病中，运动障碍和较大的呼吸MN(失神经)的丧失 肌肉的基础是MN和NMJ突触丢失和线粒体功能障碍(体积密度降低， 碎片化和活性)。此外，我们还将尝试两种方法来改善突触的作用 在AD和衰老中，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 在相同基因的Fischer 344大鼠和AD模型(TgF344-AD)中直到系统水平的行为 背景资料。在目标1中，我们将评估兴奋性和抑制性突触丢失，树突棘和树突棘丢失， 舌下结节和膈结节的存活率。此外，我们还将评估去神经、骨质疏松症和 衰老和阿尔茨海默病患者舌头和糖尿病的功能损害。在目标2中，我们将评估线粒体体积 舌下、膈肌、舌和直径中SDHmax的密度、碎裂和功能 在衰老和阿尔茨海默病。在目标3中，我们将评估是否缓解突触功能障碍(通过利鲁唑)和/或 线粒体功能障碍(依达拉奉)可改善老年和AD患者呼吸性MNS和肌肉的预后。

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.