Involvement of nicotinamide phosphoribosyltransferase in both amyloidogenic and non-amyloidogenic pathways in hippocampus

Abstract

AMP-activated kinase (AMPK) and silent mating-type information regulator 2 homolog 1 (SIRT1) are the two representative enzymes involved in energy homeostasis. Concomitant action of AMPK and SIRT1 mediates various beneficial effects including suppression of Alzheimer’s disease (AD) pathophysiology. Even though these two enzymes activate each other, metformin, the most widely prescribed anti-diabetic drug, has shown to exert neurotoxic effects via AMPK activation. Therefore, I aimed to examine the effect of metformin on neuronal SIRT1 activity, as well as on AMPK. Normally, metformin-induced AMPK activation would result in concomitant SIRT1 activation via activating AMPK/nicotinamide phosphoribosyltrans-ferase (Nampt)/nicotinamide adenine dinucleotide (NAD) pathway. However, I found that metformin could not activate neuronal SIRT1 despite AMPK activation. Rather, metformin reduced the levels of Nampt and NAD, which accounts for the failure of SIRT1 activation. Metformin-induced AMPK activation increased the levels of beta-site amyloid precursor protein cleavage enzyme 1 (BACE1) and secreted beta-amyloid (Aβ). In addition, metformin-induced Nampt suppression was associated with decreased expression of tumor necrosis factor alpha converting enzyme (TACE) which promotes non-amyloidogenic pathway. These adverse effects of metformin were also identified in the brains of diabetic db/db mice. Overexpression of Nampt rescued metformin-induced neurotoxicity in vitro. Also, donepezil treatment reversed the negative effects of metformin in vitro and in vivo, by promoting Nampt/NAD pathway. Data from the current study implicate the importance of the role of Nampt in regulating amyloidogenesis; AMPK activation by metformin might be neurotoxic because it could not induce concomitant action of AMPK and SIRT1 owing to the lack of Nampt involvement in the brain contrasted with other peripheral tissues. Co-treatment of donepezil could be a proper measure to protect the brain from potential risk of promoting AD pathogenesis in diabetic patients taking metformin.