Restoring the balance: Resistance exercise-induced insulin-like growth factor-1 restores PI3K/Akt and MAPK/ERK cross-talk to ameliorate Alzheimer's disease

Alzheimer's disease (AD) remains a progressive neurodegenerative disorder without effective disease-modifying therapies. Epidemiological evidence indicates that regular resistance exercise substantially reduces AD risk, an effect potentially mediated by insulin-like growth factor-1 (IGF-1). However, the complete mechanistic pathway from exercise-induced peripheral IGF-1 synthesis to its central neuroprotective actions has not been systematically integrated. This review provides a comprehensive framework linking resistance exercise to AD amelioration through IGF-1-dependent signaling. We first detail how resistance exercise stimulates IGF-1 secretion from the liver and skeletal muscle via both endocrine (GH-IGF-1 axis) and autocrine/paracrine (mechano-sensitive MGF induction) pathways. Subsequently, we delineate three complementary routes by which circulating IGF-1 enters the brain: (1) lipoprotein receptor-related protein-1(LRP-1)-mediated transcytosis across the blood-brain barrier (BBB) coupled with activity-dependent vasodilation, (2) lipoprotein receptor-related protein-2(LRP-2)-mediated transport across the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus, and (3) passive diffusion through circumventricular organs (CVOs). Once within the central nervous system, we propose that IGF-1 exerts its therapeutic effects primarily by restoring the physiological cross-inhibitory balance between the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways. Specifically, by reactivating Akt, exercise-induced IGF-1 suppresses GSK-3β-driven tau hyperphosphorylation, while simultaneously tempering pathological MAPK/ERK overactivation, thereby reducing β-amyloid (Aβ) generation and neuroinflammation. This rebalancing action further promotes Aβ clearance, enhances synaptic plasticity, and counteracts neuronal apoptosis. Notably, we critically discuss the context-dependent "double-edged sword" nature of IGF-1 signaling, where excessive or mistimed activation may exacerbate late-stage pathology, underscoring the need for stage-specific interventions. In summary, this review integrates the peripheral synthesis, multi-route central delivery, and pathway-rebalancing mechanisms of exercise-induced IGF-1, providing a mechanistic rationale for personalized resistance exercise prescriptions as a non-pharmacological strategy to combat AD.