Exploring the Therapeutic Potential of Bioactive Peptides in Modulating Tau Protein Interactions via the PI3K/Akt...

Neurodegenerative Diseases (NDs) represent a growing global health challenge, characterized by progressive neuronal loss and cognitive decline. Central to these disorders are tauopathies, characterized by abnormal aggregation and hyperphosphorylation of tau proteins, leading to synaptic dysfunction and neuronal degeneration. Among the many intracellular signaling pathways implicated in these processes, the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway plays a pivotal role in neuronal survival, synaptic plasticity, and tau phosphorylation regulation. Dysregulation of this pathway exacerbates oxidative stress, inflammation, and excitotoxic injury, thereby accelerating neurodegeneration. Recent research has highlighted the therapeutic potential of bioactive peptides in modulating tau pathology by targeting the PI3K/Akt cascade. These peptides, derived from natural food sources, marine organisms, and microbial fermentation, exhibit neuroprotective effects through multiple mechanisms, including inhibition of tau aggregation, suppression of proinflammatory mediators, enhancement of antioxidant defenses, and modulation of gut microbiota. Evidence from preclinical studies demonstrates that peptides such as curcumin-derived analogs, resveratrol, and glucagon-like peptide-1 analogs reduce tau phosphorylation and restore neuronal integrity. Furthermore, their ability to interact with signaling molecules such as GSK-3β underscores their promise as disease-modifying agents. Despite these advances, challenges remain, including low bioavailability, rapid metabolism, and limited capacity to cross the blood-brain barrier. Emerging nanotechnology-based delivery systems may overcome these barriers, enhancing peptide stability and therapeutic efficacy. This review summarizes current insights into the molecular interactions between bioactive peptides and tau proteins via the PI3K/Akt pathway and highlights their potential as innovative therapeutic agents for neurodegenerative diseases.