Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT...

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage pathway, has emerged as an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. However, although pharmacological inhibition of NAMPT may attenuate inflammatory activation, it may also reduce intracellular NAD⁺ availability, thereby exacerbating mitochondrial dysfunction and disturbances in energy metabolism. Here, we found that 6-month-old APP/PS1 mice exhibited an abnormal, cell type-specific distribution of NAMPT in the brain, characterized by reduced neuronal NAMPT and increased microglial NAMPT. This abnormality was accompanied by disrupted NAD⁺ homeostasis, marked neuroinflammatory activation, mitochondrial structural and functional impairment, increased β-amyloid (Aβ) burden, and impaired learning and memory ability. FK866 (1 mg/kg per injection, once every other day for 12 weeks) alone exerted limited effects and was insufficient to ameliorate the overall pathological phenotype. By comparison, a 12-week aerobic treadmill exercise program markedly ameliorated cognitive impairment, attenuated Aβ pathology, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function in APP/PS1 mice. More importantly, under NAMPT-inhibited conditions, exercise still preserved hippocampal NAD⁺ homeostasis and maintained significant neuroprotective effects. Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to Aβ pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD⁺ biosynthesis through the NMNAT3 pathway, as well as reduced NAD⁺ consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression.