Ferroptosis and NMDA Receptor Activity in Alzheimer's Disease: Implications for Amyloid Pathology and P‐Glycoprotein Regulation

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid‐β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N‐methyl‐D‐aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P‐glycoprotein (P‐gp), an efflux transporter involved in the Aβ clearance at the blood–brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P‐gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P‐gp‐mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.