Let-7 Family as a Mediator of Exercise on Alzheimer's Disease.

Abstract

Memory loss, and behavioral impairments. Hallmark pathological features include amyloid-beta (Aβ) plaques, tau neurofibrillary tangles, chronic inflammation, and impaired neuronal signaling. Physical exercise is increasingly recognized as a non-pharmacological intervention to attenuate Alzheimer's disease (AD) risk and progression by enhancing neuroplasticity, improving mitochondrial function, and modulating immune responses. The let-7 family of microRNAs is critically involved in AD pathology. Elevated levels of let-7b and let-7e have been reported in the cerebrospinal fluid of AD patients, with let-7b levels correlating positively with total tau and phosphorylated tau concentrations. Overexpression of let-7a enhances Aβ-induced neurotoxicity, increases neuronal apoptosis by up to 45%, and alters autophagy-related signaling via the PI3K/Akt/mTOR pathway, as shown by 1.8-fold increases in LC3-II/I ratios and 2.2-fold upregulation of Beclin-1 expression. Exercise modulates let-7 expression in a tissue-specific and context-dependent manner. Aerobic training reduces skeletal muscle expression of let-7b-5p by 30-35%, while increasing its suppressor Lin28a by 40%, thereby improving mitochondrial respiration. Overall, modulation of let-7 by exercise influences neuronal survival, autophagy, and inflammation, offering a potential mechanism through which physical activity exerts neuroprotective effects in AD. Quantitative characterization of let-7 expression patterns may support its use as a diagnostic and therapeutic biomarker, though further research is needed to establish optimal modulation strategies.