Friday, June 6, 2025
6/6/2025
Ameliorating Respiratory Neuromotor Dysfunctions in Aging and Alzheimer's Disease - 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, chest wall and abdominal muscles. This proposal leverages the extensive experience of the PI in both respiratory neuromotor systems and 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 and extrinsic tongue and external abdominal oblique muscles also suggest 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, thoracic and phrenic MNs – recruited to perform motor tasks; neuromuscular junctions; and tongue, chest, abdominal and DIAm muscles. 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 SPG302) 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, thoracic and phrenic MNs. Additionally, we will evaluate denervation, sarcopenia and functional impairments in tongue, chest, abdominal and DIAm muscles across aging and AD. In Aim 2, we will assess mitochondrial volume density (MVD), fragmentation and function (SDHmax) in respiratory MNs and in muscles in aging and AD. In Aim 3, we will assess whether mitigating synaptic dysfunction (by SPG302) and/or mitochondrial dysfunction (by edaravone) improves outcomes in respiratory MNs and muscles in aging and AD.
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