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The Potential of Ferroptosis-Targeting Therapies for Alzheimer's Disease: From Mechanism to Transcriptomic Analysis.

ABSTRACT: Alzheimer's disease (AD), the most common form of dementia, currently affects 40-50 million people worldwide. Despite the extensive research into amyloid β (Aβ) deposition and tau protein hyperphosphorylation (p-tau), an effective treatment to stop or slow down the progression of neurodegeneration is missing. Emerging evidence suggests that ferroptosis, an iron-dependent and lipid peroxidation-driven type of programmed cell death, contributes to neurodegeneration in AD. Therefore, how to intervene against ferroptosis in the context of AD has become one of the questions addressed by studies aiming to develop novel therapeutic strategies. However, the underlying molecular mechanism of ferroptosis in AD, when ferroptosis occurs in the disease course, and which ferroptosis-related genes are differentially expressed in AD remains to be established. In this review, we summarize the current knowledge on cell mechanisms involved in ferroptosis, we discuss how these processes relate to AD, and we analyze which ferroptosis-related genes are differentially expressed in AD brain dependant on cell type, disease progression and gender. In addition, we point out the existing targets for therapeutic options to prevent ferroptosis in AD. Future studies should focus on developing new tools able to demonstrate where and when cells undergo ferroptosis in AD brain and build more translatable AD models for identifying anti-ferroptotic agents able to slow down neurodegeneration.

SUBMITTER: Majernikova N

PROVIDER: S-EPMC8721139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesDespite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD.MethodsWe investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The "GOplot" package was applied to explore possible biological processes in oligodendrocytes, astrocytes, and oligodendrocyte progenitor cells (OPCs). Expression patterns and biological functions of differentially expressed genes (DEGs) from scRNA-seq data were validated in RNA sequencing data. DEGs in astrocytes interacted with ferroptosis-related genes in FerrDb. CCK-8 and EdU assays were performed to measure cell proliferation ability. ROS, Fe2+ level, mitochondrial membrane potentials, iron concentrations, and total iron binding capacity (TIBC) in serum were evaluated. Y-maze and elevated maze were used to measure anxiety-like behavior. Autonomous and exploration behaviors or learning and memory ability in mice were analyzed using open field test and novel object recognition test.ResultsMultiple clusters were identified, including oligodendrocytes, astrocytes, OPCs, neurons, microglia, doublets, and endothelial cells. Astrocytes were significantly decreased in AD, while oligodendrocytes and OPCs increased. Cell-to-cell ligand-receptor interaction analysis revealed that astrocytes, neurons, and OPCs mainly established contacts with other cells via the NRG3-ERBB4 ligand-receptor pair. GO and KEGG analyses found that astrocytes were enriched in the ferroptosis pathway. FTH1 and SAT1 in astrocytes were identified as hub mRNAs associated with ferroptosis. Serum iron concentration of 5xFAD mice was higher than that of WT, and emotional and cognitive function were significantly impaired as compared to WT. Serum iron concentration was negatively correlated with number of astrocytes and percentage of time spent entering the novelty arm in the Y-maze test, while it was positively correlated with percentage of time spent in the central area. Meanwhile, number of astrocytes was negatively correlated with percentage of time spent in the central area, while it was positively correlated with percentage of time spent entering the novelty arm.ConclusionsThrough scRNA-seq analysis, we found that ferroptosis was activated in astrocytes and may contribute to the pathophysiological process in the entorhinal cortex. FTH1 and SAT1 were identified to impact astrocyte ferroptosis. Emotional and cognitive impairment in AD was associated with astrocyte ferroptosis. Our findings provide clues to reveal the pathophysiological processes following AD at the cellular level and highlight potential drug targets for the treatment of AD.

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The Potential of Ferroptosis-Targeting Therapies for Alzheimer's Disease: From Mechanism to Transcriptomic Analysis.

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