Effect of alternating nicotinamide phosphoribosyltransferase expression levels on mitophagy and pathological symptoms in Alzheimer’s disease mouse models

Abstract

Abstract Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction. Extensive studies have demonstrated that mitochondrial dysfunction and mitophagy impairment contribute substantially to the pathogenesis of AD. Recent studies have shown that nicotinamide adenine dinucleotide (NAD+) augmentation restores mitophagy and removes the defective mitochondria. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of NAD+ synthesis. Therefore, this study aims to provide evidence for the role of the NAMPT-NAD +-silent information-regulated transcription factors-1 (SIRT1) axis in mediating mitophagy in 6-month-old APP/PS1 transgenic mice. The results showed that NAMPT expression in the hippocampus of APP/PS1 mice significantly decreased. However, NAMPT was upregulated using P7C3 (NAMPT activator), which significantly increased NAD+-SIRT1-FOXO1/3a signaling pathway, enhanced mitophagy activity, and improved mitochondrial structure and function as well as learning and memory ability. Whereas NAMPT was downregulated under the FK866 treatment (NAMPT inhibitor), therefore reversing the pathways, and even exacerbating Aβ plaque deposition level in the hippocampus of APP/PS1 mice. Our findings suggest that preventing the downregulation of NAMPT can abolish AD-related mitophagy impairment and that NAMPT represents a potential therapeutic intervention in AD pathogenesis.