Apigenin-Induced Shifts in Microglial and Astrocytic Polarization: A Potential Therapeutic Strategy for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β accumulation, tau pathology, synaptic failure, neurovascular dysfunction, mitochondrial injury and chronic neuroinflammation. While amyloid and tau remain central pathological features, the inflammatory state of the brain is now recognized as an active driver of disease progression rather than a secondary epiphenomenon. Microglia and astrocytes are the principal glial regulators of innate immunity, synaptic homeostasis, metabolic support and tissue repair in the central nervous system. In AD, these cells undergo heterogeneous activation states that include protective phagocytic and trophic programs as well as damaging pro-inflammatory, complement-mediated, inflammasome-driven and neurotoxic phenotypes. The historical M1/M2 and A1/A2 polarization frameworks are oversimplified, yet they remain useful shorthand for discussing inflammatory versus reparative glial tendencies. Apigenin, a naturally occurring flavone found in parsley, celery, chamomile and other plants, has emerged as a multi-target neuroprotective compound with antioxidant, antiinflammatory, anti-amyloidogenic, neurovascular and neurotrophic properties. Preclinical studies suggest that apigenin can reduce microglial activation, suppress CD68 expression, inhibit NF-κB and ERK signaling, disrupt NLRP3 inflammasome assembly, reduce IL-1β, IL-6 and TNF-α, preserve astrocytic morphology, attenuate astrogliosis, restore neurovascular coupling, reduce amyloidogenic processing and enhance ERK/ CREB/BDNF signaling. This review explored current evidence on apigenin-induced shifts in microglial and astrocytic polarization in AD-relevant models. We propose an integrated “glial state recalibration” model in which apigenin does not merely suppress inflammation but redirects glial responses away from chronic neurotoxicity toward controlled phagocytosis, trophic support, redox balance and barrier preservation. Despite promising mechanistic data, major translational barriers remain, including low bioavailability, uncertain brain exposure, limited clinical evidence, variable formulations, and incomplete understanding of dose-dependent glial effects. Finally, future development and prospective should prioritize brain-targeted delivery systems, human iPSC-derived glial models, single-cell multi-omics, biomarker-guided trials and combination strategies with disease-modifying AD therapies.