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Neuromuscular adaptation to exercise in Alzheimer's Disease

Award Number: K02AG088474
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Neuromuscular adaptation to exercise in Alzheimer's Disease - PROJECT SUMMARY During early stages of Alzheimer’s Disease (AD), skeletal muscle mass and function precipitously declines in comparison to those who are cognitively intact, potentially due to poor neuromuscular health. Thus, bioenergetics of peripheral tissues may have an underappreciated role in AD etiology. Exercise is an effective means to promote mitochondrial and neuromuscular health. However, whether regular exercise has therapeutic potential for delaying or preventing AD is an outstanding question. We present evidence of impaired skeletal muscle AMPK-signaling response to exercise in 5xFAD mice, a model of AD and show neuromuscular dysfunction is present at a young age before observable cognitive decline. Also, we present evidence that mitochondrial respiration does not improve following 12 weeks exercise training in 22-week-old 5xFAD mice compared to WT. In sum, impaired neuromuscular function may underlie a maladaptive bioenergetic response to exercise prior to overt manifestation of AD-like pathology. There is a critical need therefore to define adaptive neuromuscular mechanisms in relation to established neuropathological changes over the continuum of AD-like pathology to identify novel therapeutic targets. We hypothesize impaired bioenergetics precedes manifestation of overt AD- like neuropathology resulting in neuromuscular maladaptation to exercise training. We propose two aims: Aim 1) Determine neuromuscular adaptive response to endurance exercise training in AD mice before AD-like pathology. We will assess mitochondrial respiration and reactive oxygen species (ROS production in intact muscle fibers and as well as synthesis (i.e. biogenesis) and breakdown (via D2O labeling - GC/MS) of muscle mitochondria and intact sciatic nerves in 22-week-old 5xFAD and APP/PS1 male and female mice following 12 weeks voluntary wheel running (exercise training) (1a), determine pre- and post-exercise training neve- stimulated muscle function and sciatic nerve conductance in vivo, neuromuscular junction integrity (histochemistry) and mitochondrial quality (1b), assess central (hippocampus) and peripheral (plasma NfL and NMJ) neuropathology (1c), and perform untargeted metabolomics of muscle, sciatic nerve, and hippocampus following exercise training (1d). Aim 2) Determine tissue-specific and functional roles for AMPK⍺1 in AD-like etiology in 5xFAD mice. We will assess mitochondrial function, sciatic nerve conductance, proteostasis, development of neuropathology, and metabolomics in both muscle, sciatic nerve, and hippocampus at 3 and 9 months of age in muscle- and motor neuron-specific AMPK⍺1 knock-out, as well as novel gain- and loss-of- function AMPK⍺1(T172A) knock-in mice. Our findings will elucidate neuromuscular responses to exercise training in context with AD-like neuropathology and integrated isoform-specific functional roles of AMPK⍺ in AD- like etiology. These studies will provide mechanistic and integrated insight into novel roles for neuromuscular dysfunction as a sentinel for AD and provide training, career development opportunities, and protected time to establish a research program focused on mechanisms of age-related disease and healthy aging.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $152,237 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Aging Research	000	2	3/6/2026	NON-COMPETING CONTINUATION	$152,237
														Subtotal = $152,237

Issue Date FY: 2025 ( Subtotal = $152,237 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Aging Research	000	1	6/23/2025	NEW	$152,237
														Subtotal = $152,237

Grand Total All Awards = $304,474

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Neuromuscular adaptation to exercise in Alzheimer's Disease

Award Number: K02AG088474

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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