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    Fasted-State Aerobic Exercise Enhances Cognition and Hippocampal BDNF Signaling in an Alzheimer's Disease Rat Model
    (Springer/Plenum Publishers, 2025) Kirkbir, Fatih; Atasoy, Taner; Khodadadai, Davar; Sajedi, Heidar; Keskin, Ozlem; Babaie, Mohammad
    Alzheimer's disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impact of exercise in the fasted state remains understudied. This study compared the effects of four weeks of moderate-intensity treadmill running in either a fasted or a normal fed state on cognitive function and hippocampal BDNF signaling in an amyloid-beta (A beta)(1-42)-injected rat model of AD. Twenty-month-old male Wistar rats were allocated into five groups (n = 12 each): AD, AD plus IF (ADIF), AD plus exercise training (ADET), AD plus IF plus exercise training (ADIFET), and control. AD was induced by bilateral intra-hippocampal A beta(1-42) injection. Exercise interventions (fasted or fed) were conducted 5 days/week for 4 weeks. A beta injection significantly impaired learning and memory and reduced hippocampal levels of PKA, CREB, and BDNF (p < 0.001). Both fasting and exercise independently elevated plasma and hippocampal beta-hydroxybutyrate (beta HB) (p < 0.001), with the highest beta HB increase observed in the fasted-exercise group (p < 0.01). All intervention groups (ADIF, ADET, and ADIFET) demonstrated significant improvements in cognitive performance and hippocampal levels of PKA, CREB, and BDNF (p < 0.001). The combined fasting plus exercise group produced greater benefits than either IF or exercise alone (p < 0.05), and exercise alone outperformed fasting alone (p < 0.05). These findings indicate that aerobic exercise in the fasted state offers superior neuroprotective and cognitive benefits, likely via upregulation of beta HB/PKA/CREB/BDNF signaling, highlighting fasted-state exercise as a promising therapeutic approach for AD.