Targeting NAD⁺ Salvage Suppresses PBMC Inflammation to Improve Cognitive Function in Vascular Cognitive Impairment.

Abstract

Vascular cognitive impairment (VCI) is a cognitive decline attributed to vascular pathology. Human peripheral blood mononuclear cells (PBMCs) are the key drivers of immune and inflammatory responses in circulation and are thought to play an important role in VCI, but the mechanism is unclear. The nicotinamide adenine dinucleotide (NAD⁺) salvage pathway uses NAD⁺ breakdown products to synthesize new NAD⁺ and maintain its cellular levels. Dysregulation of this pathway may disrupt cellular metabolism and immune balance, contributing to disease. Here, we investigated whether peripheral inflammation triggered by PBMCs is linked to the aberrant NAD⁺ metabolism that occurs in VCI. Targeting the NAD⁺ salvage pathway was also explored as a potential therapeutic strategy for VCI. PBMCs from patients with VCI or controls were subjected to RNA sequencing and cultured with autologous serum. The levels of proinflammatory cytokines in PBMCs and key components in the NAD⁺ salvage pathway were measured. These parameters were assessed in a VCI mouse model. The 5'-Phosphoribosyl-pyrophosphate (PRPP), a critical substrate for NAD⁺ salvage biosynthesis, was administered, and its therapeutic effects on cognitive function were evaluated. Peripheral PBMCs from VCI patients showed elevated proinflammatory cytokine levels, reduced iNAMPT (intracellular nicotinamide phosphoribosyltransferase) activity, and lower NAD⁺ levels, whereas eNAMPT (extracellular NAMPT) levels were significantly higher. Pharmacological inhibition of eNAMPT with FK866 reduced inflammation in VCI PBMCs. Additionally, blocking TLR4 or CCR5 alleviated the proinflammatory response triggered by eNAMPT. In the VCI mice model, the NAD⁺ salvage pathway was impaired in PBMCs, which exhibited proinflammatory activity. 5'-phosphoribosyl-pyrophosphate administration restored NAD⁺ levels, suppressed inflammation, and improved cognitive function. Our findings suggest peripheral inflammation driven by impaired NAD⁺ salvage and elevated eNAMPT levels in PBMCs plays a key role in VCI pathogenesis. Restoring NAD⁺ homeostasis via 5'-phosphoribosyl-pyrophosphate treatment significantly improved cognition in VCI mice, highlighting NAD⁺ salvage as a potential therapeutic target.