Intermittent Fasting Potentiates Aerobic Exercise to Reduce Hippocampal Amyloid Burden and Oxidative Stress via Suppression of NF-κB/NLRP3 Signaling in an Aβ-Injected Rat Model
Oxidative Medicine and Cellular Longevity, vol.2026, no.1, 2026 (Scopus)
- Publication Type: Article / Article
- Volume: 2026 Issue: 1
- Publication Date: 2026
- Doi Number: 10.1155/omcl/9921337
- Journal Name: Oxidative Medicine and Cellular Longevity
- Journal Indexes: Scopus, BIOSIS, Compendex, EMBASE, MEDLINE
- Keywords: aerobic exercise, Alzheimer’s disease, cognitive function, hippocampus, intermittent fasting, NLRP3 inflammasome, β-hydroxybutyrate
- Istanbul Gelisim University Affiliated: Yes
Abstract
NOD-like receptor protein 3 (NLRP3) inflammasome-driven neuroinflammation contributes to Alzheimer’s disease (AD) progression, yet effective strategies to target this pathway are limited. We investigated whether aerobic exercise performed in a fasted state, rather than the fed state, would potentiate β-hydroxybutyrate (BHB)-dependent inhibition of NLRP3 inflammasome signaling. Twenty-month-old male Wistar rats were randomly assigned to five groups: AD, AD + intermittent fasting (ADIF), AD + aerobic exercise (ADAE), ADIF + aerobic exercise (ADIFAE), and sham-injected control (SC). AD-like pathology was induced by bilateral intrahippocampal injection of amyloid-β (Aβ)1–42. The IF regimen consisted of a daily 14-h fast (06:00–20:00). Exercise consisted of moderate-intensity treadmill running (5 days/week for 4 weeks), either in the fed state or after ∼12.5 h of fasting. Aβ injection impaired spatial learning and memory, elevated soluble Aβ1–42 (sAβ), malondialdehyde (MDA), NF-κB, NLRP3, caspase-1, interleukin-1β (IL-1β), and IL-18, and reduced superoxide dismutase (SOD) activity and brain-derived neurotrophic factor (BDNF) expression in the hippocampus (p < 0.05). Both IF and exercise partially reversed cognitive impairments by reducing sAβ and oxidative stress, increasing BHB, suppressing NF-κB/NLRP3 signaling, and restoring BDNF (p < 0.05), while fasted-state exercise produced significantly larger effects than either intervention alone (p < 0.05). Our findings suggest that performing exercise in a fasted state provides complementary metabolic, anti-inflammatory, and cognitive benefits that exceed those of either intervention alone. This combined regimen may represent a promising nonpharmacological strategy for targeting metabolic-immune and neurotrophic pathways relevant to AD progression.