Revisiting the intersection of microglial activation and neuroinflammation in Alzheimer?s disease from the perspective of ferroptosis

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic neuroinflammation with amyloid beta-protein deposition and hyperphosphorylated tau protein. The typical clinical manifestation of AD is progressive memory impairment, and AD is considered a multifactorial disease with various etiologies (genetic factors, aging, lifestyle, etc.) and complicated pathophysiological processes. Previous research identified that neuroinflammation and typical microglial activation are significant mechanisms underlying AD, resulting in dysfunction of the nervous system and progression of the disease. Ferroptosis is a novel modality involved in this process. As an iron-dependent form of cell death, ferroptosis, characterized by iron accumulation, lipid peroxidation, and irreversible plasma membrane disruption, promotes AD by accelerating neuronal dysfunction and abnormal microglial activation. In this case, disturbances in brain iron homeostasis and neuronal ferroptosis aggravate neuroinflammation and lead to the abnormal activation of microglia. Abnormally activated microglia release various pro-inflammatory factors that aggravate the dysregulation of iron homeostasis and neuroinflammation, forming a vicious cycle. In this review, we first introduce ferroptosis, microglia, AD, and their relationship. Second, we discuss the nonnegligible role of ferroptosis in the abnormal microglial activation involved in the chronic neuroinflammation of AD to provide new ideas for the identification of potential therapeutic targets for AD.