The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential

Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.