Conditioning knockout of nampt gene in mouse hippocampus neuron induces neuro⁃degeneration and cognitive deficiency

OBJECTIVE Nicotinamide phos⁃phoribosyltransferase(NAMPT)is the key en⁃zyme in the NAD(nicotinamide adenine dinucleo⁃tide)salvaging synthesis pathway.The level of NAMPT and NAD decreases during ageing,which causes neurodegenerative diseases.How⁃ever,the study of neuron-and region-specific ge⁃netic disturbance of NAMPT on cognition impair⁃ment is still lacking.This study was to explore the consequences and mechanisms of hippo⁃campus CA1 neuron-specific knockout of NAMPT on mouse cognitive functions.METH⁃ODS Floxed three-month old Nampt(Namptflox/flox)mice were used,and injected rAAV-hSyn-Cre-APRE-pA into the hippocampus CA1 region to specifically knockout the nampt gene.The learn⁃ing and memory of mice was determined at one-month after the intracerebral injection of AAV.We used immunofluorescence and trans⁃mission electron microscopy to detect neuronal injury.Western blotting and ELISA were used to measure the change of protein level and small molecule level.RESULTS One month after the knockout of nampt gene,the level of NAD signifi⁃cantly decreased in mouse hippocampus.The hippocampus dependent cognition of mice was also significantly decreased when compared to the wild type mice.However,the locomotor ac⁃tivity and anxiety behavior remained un⁃changed.Though there was no neuronal loss,and the neuronal cell bodies remained morpholog⁃ically intact.The level of Tau and MAP2 signifi⁃cantly decreased and degenerative change was found by using transmission electron micro⁃scope,which indicating the injury of both den⁃drites and axons.Meanwhile,the neuronal injury increased the neuroinflammation indicated by the activation of astrocyte and microglia.CON⁃CLUSION The decline of NAMPT and NAD causes neurodegeneration and cognition impair⁃ment of mice.