Related Mechanisms: Neuroinflammation, Microglial Activation, Blood-Brain Barrier Breakdown
NETosis is a specialized form of cell death in neutrophils that results in the release of neutrophil extracellular traps (NETs) — webs of chromatin fibers decorated with antimicrobial proteins including neutrophil elastase (NE), myeloperoxidase (MPO), and histones[1]. Originally described as a defense mechanism against pathogens, dysregulated NETosis has been increasingly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD)[2].
Neutrophil activation triggers a cascade of events leading to NET release:
An alternative, non-lytic pathway where NETs are released from viable neutrophils, involving nuclear envelope budding and nuclear-derived vesicles[4].
| Component | Function |
|---|---|
| DNA backbone | Structural scaffold for NETs |
| Neutrophil elastase (NE) | Proteolytic degradation of pathogens |
| Myeloperoxidase (MPO) | H2O2-dependent antimicrobial activity |
| Citrullinated histones | Promote chromatin decondensation |
| LL37 | Antimicrobial peptide |
| Cathepsin G | Proteolytic activity |
Multiple studies have documented elevated NET markers in AD patients:
| Drug/Compound | Target | Status |
|---|---|---|
| Cl-amidine | PAD4 | Preclinical |
| GSK-484 | PAD4 | Preclinical |
| Sivelestat | NE | Approved for ARDS |
| Omega-3 fatty acids | NETosis modulation | Clinical trials |
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Fang L, et al. NETosis in amyotrophic lateral sclerosis. Neurobiology of Aging. 2021. ↩︎
Gulce M, et al. Neutrophil extracellular traps in multiple sclerosis lesions. Neurology Neuroimmunology Neuroinflammation. 2022. ↩︎