Accelerated Sarcopenia in Early Alzheimer's Disease

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Summary: Accumulating evidence indicates that AD patient physical function gradually declines long before cognitive symptoms warrant a clinical diagnosis of dementia. These early changes often develop in regions that promote and coordinate motor function. Located throughout the central nervous system, they extend via peripheral nerve pathways into musculoskeletal structures. Elucidating these motor mechanism(s) may point toward effective AD interventions. In AD, loss of lean muscle mass precedes brain atrophy and cognitive impairment by several years. AD patients show reduced physical activity, suggesting that associated behavioral changes may result in loss of lean mass. However, even after controlling for physical activity levels, lean mass is independently associated with brain volume, so the decline in physical activity observed in AD does not fully explain accelerated loss in muscle mass and strength (sarcopenia) in early AD. We propose that damage to brainstem sympathetic neurons (SNs), which regulates cognitive and skeletal muscle function, leads first to sarcopenia, then cognitive impairment. We propose that a subgroup of pontine noradrenergic neurons (A5) that project to spinal cord intermediolateral column (IML) preganglionic and, through them, to postganglionic SN and hindlimb muscles (Sympathetic Neurons Projecting to Hindlimb Muscles, SNPHLM), regulates motoneuron function, neuromuscular junction (NMJ) transmission, and skeletal muscle innervation, mass, and strength. The remaining A5 neurons synapse with several targets, including the locus coeruleus (LC) neurons (A6), which are essential to maintaining cognitive function,but not with the NMJ. With AD, A5 SNPHLM become susceptible to cumulative damage, which accounts for early motor deficits. Optogenetics, chemogenetics, and viral vector retrograde neuron labeling provide new opportunities to define the role of A5 SNPHLM in AD muscle pathology and function. The aims of this project are: (1) To define the role of A5 SNPHLM in muscle motor denervation, impaired NMJ transmission, decreased norepinephrine (NE) release at the NMJ, and diminished adrenoceptor GPCR- mediated signaling in the early, middle, and late stages of AD; and (2) To determine whether chemogenetic modulation of A5 SNPHLM at various stages of AD enhances skeletal muscle sympathetic and motor innervation and delays or reverses accelerated sarcopenia. This project will define the role of central autonomic neurons in AD sarcopenia and predict disease progression. Analysis of autonomic central regulators of skeletal muscle structure and function will enable detection of predementia AD and formulation of effective treatments for each disease stage.