Journal of Neuroinflammation最新文献

Background: Triggering receptor expressed on myeloid cell-2 (TREM2) signaling promotes disease-associated microglia (DAM) and phagocytosis in neurodegenerative diseases. Traditional anti-TREM2 agonist antibodies block receptor shedding, lowering soluble TREM2 (sTREM2) and leading to mixed outcomes. We developed 03O05, a ligand-mimetic anti-TREM2 agonist antibody that activates TREM2 while preserving physiological shedding.

Methods: Binding epitope and cross-reactivity were defined by Bio-Layer Interferometry (BLI) and epitope mapping/mutagenesis. Functional activity was assessed using nuclear factor of activated T cells luciferase reporter (NFAT-luciferase), in vivo DAP12 phosphorylation, and microglial phagocytosis. In vivo effects on sTREM2 levels were evaluated in wild-type (WT), human TREM2 knock-in, and 5xFAD mice by ELISA. Amyloid-beta (Aβ) plaque clearance, microglial state and neuronal health were evaluated in 5xFAD model. Remyelination and microglial status were assessed in the cuprizone model.

Results: Anti-TREM2 antibody 03O05 binds a conformational epitope (M41-W44, L89) within the immunoglobulin-like domain, distal from the cleavage site, activates TREM2 signaling in vitro and in vivo, and enhances phagocytosis. A single dose treatment of 03O05 increased sTREM2 in serum and brain of WT and human TREM2 knock-in mice. In 5xFAD mice, chronic 03O05 treatment elevated serum and brain sTREM2, promoted clearance of filamentous Aβ plaques, reduced microgliosis while enhancing microglial phagocytosis, and ameliorated neuronal dystrophy. In the cuprizone model, 03O05 enhanced microglial phagocytosis and promoted remyelination by reducing degraded myelin basic protein (MBP) during recovery.

Conclusions: Unlike stalk-binding anti-TREM2 agonist antibodies, 03O05 preserves ectodomain shedding, leading to transient receptor activation and increased sTREM2 levels. This approach promotes a neuroprotective microglial phenotype without inducing neuroinflammation, reduces amyloid pathology and neuronal dystrophy, as well as supports remyelination in multiple sclerosis (MS). These findings suggest the therapeutic potential of shedding-permissive TREM2 agonism in neurodegenerative disease.

Ozone (O₃) is a significant global air pollutant. Recent epidemiological studies have established a correlation between O₃ exposure and an increased risk of neurological disorders. However, the underlying mechanisms by which O₃ induces cognitive deficits remain unclear. This study demonstrated that exposure to environmentally relevant O₃ levels resulted in significant cognitive impairment in mice. These deficits arose from hippocampal synaptic injury, characterized by reduced dendritic spine density, disrupted synaptic ultrastructure, and impaired long-term potentiation. Mechanistically, O₃ activated the liver complement pathway, leading to increased levels of complement component 3 (C3) and its subsequent release into the bloodstream. Furthermore, O₃ compromised the integrity of the blood-brain barrier, allowing peripheral C3 to infiltrate the hippocampus. Notably, C3 served as a key signal that triggered local pro-inflammatory microglial activation and enhanced their phagocytosis of excitatory synapses, ultimately resulting in synaptic loss and cognitive decline. Importantly, both the microglial inhibitor minocycline and liver-specific C3 knockdown suppressed pro-inflammatory microglial activation and restored synaptic plasticity and cognitive function. These findings systematically reveal a novel liver-brain axis in O₃ neurotoxicity, whereby peripheral C3 drives central microglial phagocytosis of excitatory synapses, offering new mechanistic insights and potential therapeutic targets for O₃-related neurological diseases.