Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.

Microglial advances in Parkinson's disease.

Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases

The protective and deleterious roles of NETs are investigated and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity are investigated, offering valuable insights for potential applications in clinical practice.

Parkinson’s Disease, Microglia, and Extracellular Matrix Remodeling

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets.

Microglial dysfunction and NLRP3 inflammasome signaling in Alzheimer’s disease: mechanistic insights into neuroinflammation and neurodegeneration

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition characterized by the accumulation of amyloid-β (Aβ), tau pathology, synaptopathy, and neuron loss. Recent studies suggest that Neuroinflammation is a critical part of the disease process rather than an accompanying feature of the mentioned pathological changes. Microglia, the immune cells of the central nervous system, respond to amyloid-beta and pathological tau and exhibit functional alterations leading to the transition from their initial anti-inflammatory and neuroprotective function to chronic inflammation. Persistent activation of microglia is linked with the inability to clear abnormal proteins, excessive complement-dependent synaptic loss, secretion of cytokines, activation of astrocytes, and neuronal damage. Various inflammatory pathways play their roles, and one of the most prominent is the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome leads to the recruitment of apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 activation, followed by interleukin-1β (IL-1β) and IL-18 maturation and gasdermin D (GSDMD) cleavage, contributing to pyroptosis and inflammatory processes. The current review will cover changing role of microglia in AD progression, interactions between Aβ, tau, and inflammatory signaling pathways as well as molecular mechanisms of NLRP3 Inflammasome activation. Furthermore, it will discuss new approaches that could be used for modulations of NLRP3 inflammasome signaling, including selective small molecule inhibition, caspase-1 targeting, natural compound use, repurposed drugs, and new drug delivery systems. Specifically, the ability to cross blood-brain barrier (BBB), safety, translational challenges, and dissimilarity between animal models and humans' AD will be discussed in this context. Overall, targeting dysregulated Neuroinflammation, including NLRP3 inflammasome activation, could serve as an alternative approach to existing protein-directed treatment methods.

Pyroptosis in Alzheimer's disease: Mechanisms and neuroinflammatory networks.

Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.

Microglia and neuroinflammation: An in-depth analysis from functional diversity to disease mechanisms.

BACKGROUND Microglia are essential regulators of central nervous system homeostasis and participate in immune surveillance, inflammatory regulation, phagocytosis, metabolic adaptation, and tissue repair. Recent single cell and spatial omics studies have revealed extensive microglial heterogeneity, challenging the traditional M1/M2 classification. However, the functional significance and therapeutic potential of distinct microglial states remain highly context dependent. METHODS This review summarizes recent advances in microglial biology across acute brain injury, neurodegenerative and demyelinating disorders, central nervous system infections, and psychiatric and neurodevelopmental diseases. Evidence from multiomics studies, genetic approaches, functional experiments, and emerging therapeutic strategies was integrated to evaluate mechanisms and translational challenges. RESULTS Microglial responses represent dynamic functional programs rather than fixed beneficial or detrimental phenotypes. Their effects on inflammation, phagocytosis, immune regulation, and tissue repair are determined by disease stage, anatomical location, and local microenvironment. Although microglia targeted therapies, including signaling modulation, depletion and repopulation, replacement strategies, and targeted delivery systems, show promise, clinical translation remains limited by insufficient human validation, model differences, and incomplete understanding of spatiotemporal regulation. CONCLUSIONS Microglial function should be interpreted within a context dependent framework integrating cellular state, functional outcome, disease stage, and therapeutic timing. Future studies should focus on cell specific validation and human translational approaches to develop precise microglia directed therapies. HIGHLIGHT Microglial responses are dynamic functional programs shaped by disease context, anatomical location, and temporal progression rather than fixed phenotypes. Single cell and spatial omics reveal extensive microglial heterogeneity, but functional validation remains essential to distinguish molecular states from biological outcomes. Context guided microglial modulation, including targeted delivery, immune regulation, depletion, and replacement strategies, provides new opportunities for precision therapy.