Brain Glycogen - Metabolism, Mechanisms, and Therapeutic Potential

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This is an Administrative Supplement request in response to NOT-NS-21-040 for “Collaborative Activities to Promote Sleep/Circadian Research in ADRD” for R35NS116824 entitled “Brain Glycogen – Metabolism, Mechanisms, and Therapeutic Potential.” The requested funds are to perform metabolomics, histology, and RNA-sequencing experiments proposed within the scope of R35NS116824 on Alzheimer's disease mouse models with the addition of including sleep disruption to the methods. The parent grant focuses on defining how aberrant intracellular glycogen-like aggregates, known as polyglucosan bodies (PGBs), impact neurodegeneration. The work is centered on both Alzheimer's disease and the childhood dementia Lafora disease with efforts to define how perturbations in metabolism impact disease progression and test a pre- clinical therapeutic option to ablate PGBs and test the biological outcome. We hypothesize that sleep fragmentation will increase PGB formations and our preliminary data strongly suggests that increased PGBs will negatively impact brain metabolism. A significant strength of this supplement is that it brings together two principle investigators that have non-overlapping and complementary expertise and who have not collaborated together in the past. The supplement will also utilize the wealth of expertise and resources provided by the UK Alzheimer's Disease Center (ADC). In this supplement, we will utilize our extensive expertise with PGBs to: Aim 1: Define PGBs, metabolic profiles, gene expression, and AD hallmarks during disrupted sleep. Aim 2: Assess AD hallmarks during disrupted sleep in AD animals treated with VAL-0417.