Exercise Plus NAMPT Inhibitor Clears Amyloid and Curbs Brain Inflammation in Alzheimer's Mice

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a key regulator of both cellular energy metabolism and neuroinflammation. In Alzheimer's disease (AD), disrupted NAD+ homeostasis contributes to mitochondrial dysfunction, oxidative stress, and chronic microglial activation. This study examined whether combining aerobic exercise with FK866, a selective NAMPT inhibitor, could safely exploit the anti-inflammatory properties of NAMPT suppression while avoiding its metabolic drawbacks in the APP/PS1 mouse model of AD.

Six-month-old APP/PS1 mice displayed a striking cell-type-specific NAMPT abnormality: neuronal NAMPT was reduced while microglial NAMPT was elevated. This pattern was associated with NAD+ imbalance, pronounced neuroinflammatory activation, structural and functional mitochondrial impairment, increased beta-amyloid (Aβ) burden, and deficits in learning and memory. Five groups of male mice (wild-type controls, AD-saline, AD-exercise, AD-FK866, and AD-exercise+FK866) underwent a 12-week intervention beginning at 3 months of age. Exercise consisted of moderate-intensity treadmill running at 12 m/min, 45 min/session, 5 days/week. FK866 was given intraperitoneally at 1 mg/kg every other day.

FK866 alone produced only limited and insufficient improvements across the AD pathological phenotype. By contrast, aerobic exercise alone substantially ameliorated cognitive impairment, reduced Aβ plaque load, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function. Importantly, exercise maintained hippocampal NAD+ homeostasis even under conditions of NAMPT inhibition, suggesting that exercise activates alternative or compensatory NAD+ biosynthetic routes.

The combined exercise plus FK866 intervention outperformed exercise alone on several specific indices: Aβ pathology markers, neuroinflammatory signaling, oxidative stress parameters, and mitochondrial damage indicators showed further improvement. Mechanistically, these additive benefits appeared linked to upregulation of NMNAT3 (an alternative NAD+ biosynthetic enzyme), and to reduced expression of CD38 and PARP1, two major NAD+-consuming enzymes that drive neuroinflammatory NAD+ depletion in the AD brain.

These findings establish aerobic exercise as a systemic physiological intervention capable of sustaining NAD+ metabolic resilience, thereby creating a permissive environment in which NAMPT inhibition can exert anti-inflammatory effects without compounding mitochondrial or energetic deficits. The study provides a mechanistic rationale for combining exercise with targeted pharmacological interventions in AD treatment strategies, though translation to human patients requires further investigation.