Investigating the Relation Between NAD+ Biosynthesis and Glucose Metabolism in a Mouse Model of Alzheimer's Disease using In Vivo 2H MRS

Motivation: Glucose hypometabolism due to reduced tri-carboxylic acid (TCA) cycle flux is a characteristic pathology in Alzheimer's disease (AD). Since, redox balance (NAD+/NADH) plays a crucial role in regulation of TCA cycle, studying NAD+ biosynthetic pathway and its relation to glucose metabolism in AD can provide a therapeutic target. Goal(s): To monitor glucose metabolism and nicotinamide phosphoribosyltransferase (NAMPT) levels in APPNL-F/NL-F mice. Approach: Monitoring cerebral 4,4-2H2-Glx labeling from 6,6'-2H2-Glucose using pulse-acquired 2H-MRS and NAMPT immunostaining. Results: Reduced labeling of 4,4-2H2-Glx in AD mice suggests compromised TCA cycle flux and glucose hypometabolism which could be attributed to reduced NAMPT levels and hence NAD+. Impact: This preliminary study supports the loss of NAMPT levels as a possible underlying cause of compromised neuroenergetics and metabolism in AD and potential of NAMPT activators in alleviating the symptoms of the disease by upregulating glucose metabolism.