Ceren Perihan Gonul

Neuroinflammatory processes in the brain are mediated mainly by microglia, which are the innate immune cells of the central nervous system (CNS). In the developing brain, microglia also contribute to neurogenesis in addition to their numerous other roles in homeostasis maintenance, phagocytosis, and synaptic pruning. The anti-inflammatory phenotype of microglia has been shown to stimulate neuronal differentiation. As extracellular vesicles have emerged as a significant way of communication within the brain, we hypothesized that small extracellular vesicles (sEVs) from microglia interact with neural progenitor cells (NPCs) and we have demonstrated the uptake of PKH67-labelled sEVs by NPCs. Microglial anti-inflammatory phenotype secretes sEVs with differential content compared to control sEVs, which in turn affects the differentiation of NPCs. In the present study, we have demonstrated that sEVs from control and IL-4-induced N9 microglia have differential miRNA content. Furthermore, NPCs derived from CGR8.0 ESC line enhanced neurite outgrowth and neuronal differentiation when exposed to sEVs from IL-4-induced microglia. Since the increase in neuronal markers and neurite outgrowth in recipient cells was mitigated by the miR-34a-5p inhibitor, we have concluded that IL-4-induced sEVs promote neuronal differentiation through miR-34a-5p. Our findings offer new insights into the regulation of neuronal cell fate in expression levels by linking immune cell signaling, miRNA-mediated gene regulation and intercellular communication.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders characterized by the accumulation of amyloid‐β (Aβ) peptide and phosphorylated tau protein in the brain. Despite intensive efforts, early diagnosis and monitoring of AD remain challenging due to the lack of reliable biomarkers that can detect the disease in its preclinical stages. As a result, there exists a requirement for novel approaches to the diagnosis and treatment of the disease. Extracellular vesicles provide the transfer of Aβ peptides and tau proteins between the cells and participates in the spreading/propagation of disease pathology. Neuron‐derived extracellular vesicles (NDEVs) that are found in plasma have emerged as promising candidates, especially for biomarker studies on neurodegenerative diseases because they are reachable and comparable with cerebrospinal fluid (CSF) studies. In addition to known proteins, synaptic proteins, transcription factors, or microRNAs have been suggested as new biomarkers, aiming to help differential or early diagnosis. Beyond their involvement in AD pathology, NDEVs also play essential roles in neurodevelopment and aging by mediating cell‐to‐cell communication and regulating processes such as synaptic formation, neuronal differentiation, and neuroinflammation. Age‐related alterations in EV composition and secretion may contribute to the decline in neuroplasticity, thereby increasing susceptibility to neurodegenerative diseases like AD. Several challenges such as heterogeneous isolation of NDEVs limit the widespread clinical application of them as biomarkers for AD. Furthermore, the lack of standardized protocols for vesicle isolation and molecular analysis poses a barrier to reproducibility and clinical validation. The aim of this review is to elucidate the role of NDEVs in AD pathogenesis in comparison with their functions in neurodevelopment and aging, evaluate their potential as biomarkers for early diagnosis, while addressing the challenges in their isolation, characterization, and clinical application.

Microglia are the tissue-resident immune cells of the central nervous system. As a part of the innate immune response, NLR Family Pyrin Domain Containing Protein 3 (NLRP3) inflammasome activation leads to cleavage of caspase-1 and triggers secretion of proinflammatory cytokines and may also result in pyroptotic cell death. Inflammasome activation plays a crucial role in inflammatory conditions; aberrant activation of inflammasome contributes to the pathogenesis of neurodegenerative diseases. Diethyl Maleate (DEM) is a promising antiinflammatory chemical to alleviate inflammasome activation. In this study, NLRP3 inflammasome was activated in N9 murine microglia via 1 µg/ml LPS (Lipopolysaccharide) for 4 h and 5 mM ATP (Adenosine 5′-triphosphate) for 1 h, respectively. We demonstrated that 1 h pretreatment of DEM attenuated NLRP3 inflammasome activation in microglial cells. Besides, mitochondrial ROS decreased upon DEM pretreatment in inflammasome-induced cells. Likewise, it ameliorated pyroptotic cell death in microglia. DEM is a potent activator of Nrf2 transcription factor, the key regulator of the antioxidant response pathway. Nrf2 has been a significant target to decrease aberrant inflammasome activation through the antioxidant compounds, including DEM. Here, we have shown that DEM increased Nrf2 translocation to the nucleus, resulting in Nrf2 target gene expression in microglia. In conclusion, DEM is a promising protective agent against NLRP3 inflammasome activation.