Alzheimer's disease supplement to NS070899 linking polyglucosans to AD

University Of Kentucky, Lexington KY

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Linked publications & trials

Abstract

This is an Administrative Supplement request in response to NOT-AG-18-008 for ?Alzheimer's Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease? for R01NS07899 entitled ?Regulation, signaling, and dynamics of glucan phosphatases.? The requested funds are to perform experiments proposed within the scope of R01NS07899, but were not originally focused on Alzheimer?s disease. The parent grant focuses on defining the molecular mechanism of Lafora disease (LD). LD is a fatal, neurodegenerative glycogen storage disease. The pathogenic agent and a hallmark of LD are aberrant, glycogen-like intracellular polyglucosan body (PGB) inclusions. In the parent grant, we propose to: 1) define these PGBs in terms of their physiochemical make-up, 2) define the metabolic machinery that generates them, and 3) develop putative therapeutics to remove them. Recent work has identified PGBs in Alzheimer?s disease patient samples and we see that these PGBs are localized in similar regions as tau. A significant strength of this supplement is that it brings together three PIs that have non- overlapping and complementary expertise. 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: Establish the physiochemical properties of PGBs in Alzheimer?s disease models. Aim 2: Define central carbon metabolism using steady state metabolomics in Alzheimer?s models. Aim 3: Identify and develop an amylase to degrade Alzheimer?s disease PGBs as a putative therapeutic.