High-intensity interval training modulates APP expression and reduces neuronal apoptosis in a β-amyloid-induced model of Alzheimer’s disease: hippocampal evidence

High-intensity interval training (HIIT) has emerged as a promising non-pharmacological strategy for neuroprotection, although its molecular effects in Alzheimer’s disease (AD) remain unclear. This study investigated the effects of HIIT on gene expression (FNDC5, PPARGC1A, APP), protein expression, cognitive performance, and neuronal apoptosis in a β-amyloid-induced rat model of AD. Sixty male Wistar rats were divided into four groups: sham sedentary (SS), sham trained (ST), Alzheimer sedentary (AS), and Alzheimer trained (AT). AD-like pathology was induced by intrahippocampal infusion of β-amyloid (Aβ1–42). Animals underwent an 8-week HIIT protocol. Gene expression was assessed by qPCR using the ΔCt method, and statistical analyses were performed using two-way ANOVA or mixed-design ANOVA followed by Tukey’s post hoc test. HIIT significantly increased PPARGC1A expression ( p < 0.05), while FNDC5 gene expression remained unchanged ( p > 0.05). However, FNDC5 protein expression was increased in trained groups. APP gene expression was significantly reduced at the transcriptional level ( p < 0.05), whereas APP protein abundance differed among experimental conditions without a uniform training-related reduction. HIIT improved physical performance ( p < 0.0001) and reduced hippocampal neuronal apoptosis ( p < 0.05). In the Morris water maze, improvement was observed only within the Alzheimer-trained group, with no significant differences between groups. HIIT was associated with molecular and cellular adaptations consistent with a neuroprotective response in this β-amyloid-induced model, including metabolic-pathway modulation, reduced APP transcription, and attenuated neuronal apoptosis. These effects were not accompanied by robust between-group cognitive improvement.