Ameliorating Synaptic and Mitochondrial Dysfunctions of the Respiratory Neuromotor System in 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 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.
