Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging

摘要

Abstract In response to NOT-AG-20-034: “Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease”, we propose to take advantage of state-of-the art noninvasive imaging techniques developed at Penn in order to follow changes in brain nicotinamide adenine dinucleotide (NAD) levels over time in the well-characterized 5XFAD mouse model of Alzheimer's disease (AD) with and without a supplemental NAD precursor. These experiments will test whether changes in brain NAD concentration anticipate or correlate with cognitive deficits in live animals. Critically, the MRI-based imaging techniques employed are readily translatable to human subjects. The proposed studies fall within the scope of Aim 2 of the parent award: “Determine the downstream mechanisms that are compromised by NAD limitation and restored by supplemental precursors,” and will add substantial value to the work, as Alzheimer's disease is emerging as a key area in which NAD metabolism may have an impact. Over the past 7 years, multiple studies have demonstrated improvements in cognition in rodent models of AD after supplementing animals with either nicotinamide riboside (NR) or nicotinamide mononucleotide. However, the available data are insufficient to determine conclusively whether supplementation is increasing NAD content in affected brain regions, whether changes in NAD levels precede cognitive effects, or whether they correlate with cognitive function on an individual animal basis. In a few cases, NAD was extracted and measured from post-mortem brain samples, but this is not an ideal approach as it cannot be performed longitudinally, cannot distinguish changes in neuronal NAD concentration from changes in neuronal density, and cannot be used in humans (for obvious reasons in living patients, but also in post- mortem samples, which are almost always collected too slowly to preserve metabolites). MRI solves all of these problems and will allow us to clarify the relevance of NAD metabolism in rodents using a technique that can be readily translated to human patients. In the proposed studies, we will longitudinally follow cognition function and brain NAD levels in cohorts of 5XFAD mice that are untreated or given NR in the drinking water. Brain NAD levels will be overlaid with an MRI-based measure of glutamate concentration (“GluCEST”), which has been recently validated as a marker of synaptic density. At 9 months of age, the cohorts will be sacrificed for histological assessments of AD-related pathology and biochemical determination of metabolite concentrations. These experiments will advance the core goals of the parent award, to understand where and when NAD metabolism is important, and will test a hypothesis that could lead to desperately needed biomarkers for AD, or even a therapeutic approach to delay progression.