TRPV1-tau axis: A bidirectional regulatory mechanism linking pain sensitization and Alzheimer's disease progression and its potential for intervention.

Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by β-amyloid (Aβ) deposition and pathological tau phosphorylation and aggregation, frequently accompanied by chronic pain. Pain sensitization is closely linked to AD progression. Transient receptor potential vanilloid 1 (TRPV1), a key cation channel in pain transduction, is expressed not only in peripheral sensory neurons but also widely in central neurons and glial cells, where it contributes to pain sensitization and neuroinflammation. Emerging evidence indicates a bidirectional regulatory interplay between TRPV1 and tau, forming a "TRPV1-tau axis." This axis acts as a core molecular bridge connecting pain sensitization and AD pathology via calcium dyshomeostasis, mTOR/AMPK, PI3K/Akt/GSK3β, and neuroinflammatory pathways. TRPV1 overactivation promotes tau hyperphosphorylation and aggregation through calcium-dependent kinases, metabolic dysregulation, and inflammatory signaling. Conversely, pathological tau modulates TRPV1 expression and function via transcriptional regulation, protein interactions, and impaired axonal transport, establishing a deleterious feedback cycle. Therapeutic interventions targeting this axis, including TRPV1 modulators, tau-directed agents, anti-inflammatory drugs, and natural compounds, demonstrate potential in alleviating both pain sensitivity and cognitive deficits through multi-target mechanisms. However, clinical translation remains challenging due to issues including blood-brain barrier penetration, target selectivity, and a lack of reliable biomarkers. This review systematically outlines the bidirectional mechanisms of the TRPV1-tau axis, current intervention strategies, and translational challenges, with the goal of informing future development of disease-modifying therapies that concurrently address cognitive decline and chronic pain in AD.