Ferroptosis and pathogenesis of neuritic plaques in Alzheimer disease

Neuritic plaques are pathognomonic and terminal lesions of Alzheimer disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration, neuroinflammation, and iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid-3 protein (A3), and it is believed that during conversion, amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles However, recent evidence from human postmortem studies suggests a much different mechanism of neuritic plaque formation, where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, neurofibrillary tangles represent the corpses of iron-laden neurons that develop independently of A3 deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in the human temporal lobe during early, preclinical stages of AD. The findings have allowed the construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. Significance Statement: This review offers a novel perspective on Alzheimer disease pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. Herein, we review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and ensuing dementia. (c) 2024 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.