Metabolic Regulatory Networks in Ferroptosis During Alzheimer’s Disease, Mechanisms of Glial Cell Action, and Pathological Correlations with Neuritic Plaques

Bowen Zhang,1 Miao Zhang2 1Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 2The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of ChinaCorrespondence: Miao Zhang, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 411 Gogol Street, Harbin, People’s Republic of China, Tel +86 13845088833, Email [email protected]: Alzheimer’s disease (AD) is a neurodegenerative disease with a complex pathological mechanism, which is still poorly understood. Ferroptosis is a type of non-apoptotic programmed cell death. Many recent studies have found that ferroptosis is closely related to the occurrence and development of AD. This article explains the main theoretical basis of ferroptosis in the pathological development of AD, and systematically analyzes the synergistic pathological network of multiple pathways caused by iron metabolism disorder, abnormal lipid peroxidation, and abnormal amino acid metabolism. This article mainly focuses on the dual regulation mechanism and molecular mechanism of microglia, astrocytes, and oligodendrocytes in the process of ferroptosis. This article studies the two-way relationship between neuritic plaques (NP) and ferroptosis, and the relationship between NP and dystrophic neurites, inflammatory response, and abnormal tau phosphorylation. Based on the existing research, we propose several unanswered questions and possible targeted research directions to provide a theoretical reference for the study of AD pathogenesis and the exploration of intervention strategies.Plain Language Summary: Alzheimer’s disease is a serious brain condition that causes memory loss. One major cause of this disease is the buildup of too much iron in the brain. This excess iron harms brain cells and leads to their death. We call this specific type of cell death “iron-driven cell death.&#x201DBrain cells do not work alone. They are helped by many support cells. In Alzheimer’s disease, these support cells also get damaged by the extra iron. When they fail, they cannot protect the brain anymore. This makes the disease worse. Harmful protein clumps form in the brain. These clumps hurt memory and thinking skills.Scientists have found that certain transport systems in the brain move iron and other chemicals. Sometimes, these systems work too hard or not well enough. This imbalance causes more damage. For example, too much of a chemical called glutamate can hurt nerve cells.This review elucidates how iron, support cells, and these transport systems work together to cause Alzheimer’s disease. We also discuss new ideas for treatment. Doctors might be able to stop this iron-driven cell death. They could also fix the problems in support cells. These new methods might help slow down the disease. Our goal is to find better ways to protect the brain and help patients live healthier lives.Keywords: ferroptosis, Alzheimer’s disease, glial cells, neuritic plaques, pathogenesis