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）和自然衰老中的神经运动系统。 衰老年龄的增加与肌肉萎缩和无力（少肌症）有关，是一个重要的预测因素 慢性病和老年人死亡率的关系。衰老是AD等疾病的主要风险因素， 阻塞性睡眠呼吸暂停（OSA）。在老年人群中，肺炎的发病率是年轻人的3倍。 年龄组，AD进一步增加气道感染的发病率和严重程度。气道发病率 感染在老龄化和年龄相关的疾病无疑是有关的肌肉减少症的膈肌 （DIAm）和气道保护动作的不协调，这涉及DIAm和各种各样的 包括单独的舌肌在内的其他与发音相关的肌肉。该提案利用了广泛的 PI在呼吸神经运动系统和神经变性方面的经验。之前我们发现 DIAm肌肉减少症与较大膈运动神经元（MN）的丢失和随后的去神经支配有关， 与马达装置对最大经颅压产生的特定影响一致。我们的初步 内在（纵肌和横肌）和外在（颏舌肌）舌的观察结果 肌肉提示舌肌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损失的原因尚不清楚，但来自神经退行性疾病的线索， 受影响的MN表明突触丢失和线粒体功能障碍导致MN死亡， 对较大MN的不成比例的影响。这一建议在概念上的主要进步是， 全面评估整个运动单位：舌下神经和膈神经-招募执行运动任务; 神经肌肉接头-将神经冲动连接到肌肉;以及舌头和DIAm -效应细胞。 我们假设在老年和AD中，运动障碍和呼吸道较大MN（去神经支配）的丧失， 肌肉由MN和NMJ突触损失和线粒体功能障碍（体积密度降低， 分裂和活动）。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死亡的损失（通过利鲁唑）或线粒体功能障碍（通过依达拉奉）。 拟议的研究采用了一系列创新技术，评估范围从亚细胞 在Fischer 344大鼠和AD模型（TgF 344-AD）中， 背景在目标1中，我们将评估兴奋性和抑制性突触丢失，树突和树突棘丢失， 以及舌下神经和膈神经的存活率。此外，我们还将评估失神经支配、肌肉减少症和 在衰老和AD中舌和DIAm的功能障碍。在目标2中，我们将评估线粒体体积 舌下神经、膈神经、舌神经和DIAm中的MVD、碎片和功能SDHmax 在老化和AD中。在目标3中，我们将评估减轻突触功能障碍（通过利鲁唑）和/或 线粒体功能障碍（依达拉奉）改善了衰老和AD中呼吸MN和肌肉的结果。

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.