This administrative supplement is submitted in response to Notice Number: NOT-AG-18-008: Alzheimer's Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease. This supplement is outlines experiments to extend the parent R01, Molecular clock and skeletal muscle weakness (R01 AR066082) to determine the impact of disruption of the skeletal muscle clock on Alzheimer?s disease onset and progression. Studies of skeletal muscle have not been the primary focus of Alzheimer?s Disease research, however, there are clinical studies in the last 10 years that have observed loss of skeletal muscle mass/sarcopenia occurs at a faster rate in Alzheimer?s disease patients and this is associated with brain atrophy and diminished cognitive performance. There are also several studies with animal models of AD that demonstrate changes in skeletal muscle strength and metabolism at stages prior to the appearance of amyloid plaques in the brain. My lab has generated preliminary data that shows that skeletal muscles of our mice, mBmal1 cKO, exhibit accelerated aging phenotype with changes in expression of the secreted glycoproteins, which are known to inhibit protein aggregation of misfolded pathological proteins that are associated with AD. We propose to test the hypothesis that muscle specific loss of Bmal1, will lead to accelerated onset and progression of neurodegeneration in a mouse model of Alzheimer?s disease. In addition, we will also test the provocative concept that loss of Bmal1 in skeletal muscle is sufficient to induce AD-related changes in the brain.
The Specific Aim to be tested is:
Aim 1) To determine whether loss of Bmal1 in adult skeletal muscle will alter proteostatic networks in the hippocampus and cortex and modulate the seeding and evolution of AD pathologies. Collectively, these studies will provide new insight into the role of skeletal muscle and skeletal muscle homeostasis on the evolution of Alzheimer?s Disease pathologies.
Alterations in both muscle strength and size are recognized as co-morbidities in patients with Alzheimer?s disease. The objective of this multidisciplinary project is to test whether altered homeostasis in skeletal muscle will accelerate the onset and progression of neurodegeneration in mouse models of Alzheimer?s disease. Collectively, these studies will provide new insight into the role of skeletal muscle dysfunction on the evolution of Alzheimer?s Disease pathology.
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