Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding A(3 plaques in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-beta (A beta) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-A beta immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of A beta accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by A beta pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (App(NLGF)) mouse model of A beta amyloidosis. The CE-TOFMS analysis of plasma samples from female wildtype (WT) and App(NLGF) mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in App(NLGF) mice, and altered metabolite profiles were enriched for nicotinate/ nicotinamide metabolism. In App(NLGF) mouse brains, NAD(+) levels were unaltered, but mRNA levels of NAD+synthesizing nicotinate phosphoribosyl transferase (Naprt) and NAD(+)-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding A beta plaques in the cortex and hippocampus of female App(NLGF) mouse brains, suggesting neuroinflammation increases NAD(+) metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.