Astrocytes: Emerging Therapeutic Targets in Neurological Disorders

Objectives: Despite 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. Methods: We 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. Results: Multiple 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. Conclusions: Through 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. Full article

Major depressive disorder (MDD) is a common and complex mental disorder, that adversely impacts an individual’s quality of life, but its diagnosis and treatment are not accurately executed and a symptom-based approach is utilized in most cases, due to the lack of precise knowledge regarding the pathophysiology. So far, the first-line treatments are still based on monoamine neurotransmitters. Even though there is a lot of progress in this field, the mechanisms seem to get more and more confusing, and the treatment is also getting more and more controversial. In this study, we try to review the broad advances of monoamine neurotransmitters in the field of MDD, and update its effects in many advanced neuroscience studies. We still propose the monoamine hypothesis but paid special attention to their effects on the new pathways for MDD, such as inflammation, oxidative stress, neurotrophins, and neurogenesis, especially in the glial cells, which have recently been found to play an important role in many neurodegenerative disorders, including MDD. In addition, we will extend the monoamine hypothesis to basic emotions; as suggested in our previous reports, the three monoamine neurotransmitters play different roles in emotions: dopamine—joy, norepinephrine—fear (anger), serotonins—disgust (sadness). Above all, this paper tries to give a full picture of the relationship between the MDD and the monoamine neurotransmitters such as DA, NE, and 5-HT, as well as their contributions to the Three Primary Color Model of Basic Emotions (joy, fear, and disgust). This is done by explaining the contribution of the monoamine from many sides for MDD, such the digestive tract, astrocytes, microglial, and others, and very briefly addressing the potential of monoamine neurotransmitters as a therapeutic approach for MDD patients and also the reasons for its limited clinical efficacy, side effects, and delayed onset of action. We hope this review might offer new pharmacological management of MDD. Full article

Parkinson’s disease (PD) is a prevalent neurodegenerative aging disorder that manifests as motor and non-motor symptoms, and its etiopathogenesis is influenced by non-coding RNAs (ncRNAs). Signal pathway and gene sequence studies have proposed that alteration of ncRNAs is relevant to the occurrence and development of PD. Furthermore, many studies on brain tissues and body fluids from patients with PD indicate that variations in ncRNAs and their target genes could trigger or exacerbate neurodegenerative pathogenesis and serve as potential non-invasive biomarkers of PD. Numerous ncRNAs have been considered regulators of apoptosis, α-syn misfolding and aggregation, mitochondrial dysfunction, autophagy, and neuroinflammation in PD etiology, and evidence is mounting for the determination of the role of competing endogenous RNA (ceRNA) mechanisms in disease development. In this review, we discuss the current knowledge regarding the regulation and function of ncRNAs as well as ceRNA networks in PD pathogenesis, focusing on microRNAs, long ncRNAs, and circular RNAs to increase the understanding of the disease and propose potential target identification and treatment in the early stages of PD. Full article