TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.

Post-translational modifications in Neuroimmune cells during neuroinflammation: integrated regulatory networks and therapeutic opportunities

Neuroinflammation represents a common pathological mechanism underlying a wide range of central nervous system (CNS) disorders, encompassing neurodegenerative disorders (NDDs), ischemic stroke (IS), traumatic brain injury (TBI), and demyelinating diseases such as multiple sclerosis (MS). This process is initiated by the orchestrated responses of microglia, astrocytes, oligodendrocyte-lineage cells, neurons, brain endothelial cells, and infiltrating peripheral immune cells. Neuroinflammation can facilitate tissue repair or, conversely, perpetuate chronic inflammation and neural damage. Post-translational modifications (PTMs) serve as critical mediators linking extracellular danger signals and intracellular metabolic conditions to alterations in protein activity, stability, localization, interactions, and degradation. Notably, the biological impact of a PTM cannot be solely deduced from its classification; rather, it is contingent upon factors such as the specific enzyme responsible for its addition or removal, the identity of the substrate, the modified residue or ubiquitin-chain architecture, the subcellular localization, the cellular context, and the stage of the disease. In this review, we synthesize evidence on various PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, S-nitrosylation (SNO), and metabolite-coupled modifications, including lactylation and succinylation. We analyze their convergent and divergent roles across different neuroimmune cell types, disease-related stimuli, and temporal contexts, and investigate the mechanisms by which intercellular communication propagates PTM-dependent inflammatory signals. Special emphasis is placed on the ordered and competitive crosstalk among PTMs that modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, and JAK-STAT signaling pathways, as well as the integrity of the blood-brain barrier (BBB), oligodendrocyte differentiation, and remyelination processes. Additionally, we assess PTM-regulating enzymes as potential therapeutic targets, while highlighting current limitations such as uneven cell-specific evidence, extrapolation from non-neural systems, low modification stoichiometry, rapid turnover, tissue-processing artifacts, and the insufficiency of transcriptomic data alone to demonstrate site-specific protein modifications. The integration of single-cell and spatial multi-omics with PTM-enrichment proteomics, quantitative site-occupancy assessments, and orthogonal mechanistic validation is anticipated to facilitate the generation of PTM maps that are resolved at the cellular, site-specific, and developmental stage levels. This evidence-based framework has the potential to enhance biomarker-guided disease stratification and inform the development of more selective, brain-targeted therapeutic interventions for neuroinflammatory disorders. Not applicable

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

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.

The Role of Neuroinflammation in Alzheimer's Disease: Molecular Mechanisms and Emerging Therapeutic Approaches

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder traditionally characterized by amyloid-beta (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuronal loss. Increasing evidence indicates that neuroinflammation is not merely a secondary consequence of neurodegeneration but an important component of AD pathogenesis. This review examines the molecular and cellular mechanisms through which neuroinflammation contributes to the progression of AD, with particular emphasis on microglial activation, TREM2 and soluble TREM2 (sTREM2) signaling, NLRP3 inflammasome activation, astrocyte–microglia interactions, and blood–brain barrier dysfunction. The review further evaluates emerging therapeutic strategies aimed at modulating these pathways, including NLRP3 inhibition, TREM2/sTREM2-targeted approaches, restoration of glial homeostasis, cytokine modulation, and pro-resolving strategies. Current evidence suggests that inflammatory responses may exert both protective and detrimental effects depending on disease stage, duration, and cellular context. Consequently, broad suppression of neuroinflammation may be insufficient and potentially counterproductive. Future therapeutic development may benefit from precision immunomodulation guided by disease-stage-specific biomarkers and molecular profiling. Understanding the complex interactions between neuroinflammation, pathological protein accumulation, glial dysfunction, and neurovascular abnormalities may therefore provide new opportunities for developing disease-modifying approaches to Alzheimer’s disease.

TREM2 as a central immunometabolic hub in Alzheimer’s disease: linking microglial states, lipid stress, and disease-stage-specific intervention

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial function in Alzheimer’s disease (AD) and other neurodegenerative disorders. Genetic studies have identified rare coding variants in TREM2 as significant risk factors for late-onset AD (LOAD), highlighting the importance of disrupted microglial signaling in disease pathogenesis. Biochemically, TREM2 acts as a receptor for lipid- and damage-associated molecular patterns, recognizing anionic phospholipids, myelin-derived lipids, apolipoproteins, and aggregated amyloid-β (Aβ). It engages with adaptors like DAP12 and DAP10, activating key signaling pathways, including SYK, PI3K-AKT-mTOR, and PLCγ2, leading to microglial transcriptional and metabolic reprogramming. These processes are essential for the transition of microglia to disease-associated microglia (DAM), influencing amyloid plaque compaction and tau pathology propagation. This review aims to synthesize the latest insights into TREM2 biology, focusing on the role of TREM2 in microglial state transitions, lipid metabolism, and myelin turnover. It also examines the pathophysiological relevance of soluble TREM2 (sTREM2) and AD-associated TREM2 variants. Furthermore, the review explores the therapeutic potential of targeting TREM2, including strategies based on agonistic antibodies and modulation of receptor shedding. Beyond prior descriptive summaries, we organize these findings within a stage-resolved immunometabolic framework that links disease timing, lipid-stress context, and microglial state transitions. This framework is intended to explain why similar TREM2-directed interventions may yield different outcomes across disease stages and pathology compositions. We further highlight stage-specific translational logic, including biomarker-informed (e.g., sTREM2-guided) stratification and monitoring, to support testable and clinically actionable trial designs.

Microglia-mediated neuroinflammation in Alzheimer’s disease: mechanisms and emerging therapeutic targets

A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.