Neutrophils: From Immune Sentinels to Agents of Neurodegenerative Diseases in the Aging CNS

Neurodegenerative diseases represent one of the most pressing challenges in aging research, with advancing age the primary risk factor for disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and vascular cognitive impairment. These conditions share a backdrop of inflammaging and immunosenescence, in which chronic low-grade inflammation, blood-brain barrier dysfunction, and impaired immune resolution converge on progressive neuronal injury. Within this immune landscape, neutrophils are increasingly recognised not as short-lived peripheral responders but as dynamic regulators of central nervous system (CNS) health.Recent work shows that age reshapes neutrophil biology at multiple levels: shifts in emergency granulopoiesis and bone marrow output, altered phenotype and heterogeneity, prolonged cellular lifespan, and impaired clearance by aged macrophages. These changes prime neutrophils for dysregulated activation, infiltration across the blood-brain barrier, sustained release of granule proteins, reactive oxygen species, and proteolytic enzymes, and formation of neutrophil extracellular traps (NETs). Within the CNS, neutrophils and their secreted mediators engage microglia, astrocytes, oligodendrocytes, endothelial cells, and perivascular macrophages, influencing inflammation, synaptic function, and neuronal survival. Specific neutrophil granule proteins have also been shown to modulate amyloid beta aggregation, RAGE signalling, and microglial activation, pointing to direct mechanistic links with established neurodegenerative pathways.Despite rapid progress, the field is shaped by unresolved debates. It remains contested whether neutrophils genuinely infiltrate brain parenchyma or accumulate primarily in perivascular and meningeal compartments, whether NETs are causal contributors to neurodegeneration or downstream markers of tissue injury, and whether neutrophil-directed therapies can be deployed safely in older adults without compromising host defence. The relative weight of neutrophils as initiators, amplifiers, or responders across different age-related CNS disorders is also unsettled.This Research Topic aims to clarify how neutrophils contribute to neuroinflammation and neurodegeneration in the aging CNS. We invite studies that dissect mechanisms of neutrophil activation, trafficking, and crosstalk with CNS-resident cells; explore disease-specific roles; and evaluate translational potential as biomarkers or therapeutic targets. By integrating experimental, clinical, and systems-level evidence, the Topic seeks to define how age-driven immune remodelling shapes neurodegenerative vulnerability and where intervention is most likely to succeed. We particularly welcome contributions from groups working at the intersection of innate immunity, aging biology, and neurodegeneration.We welcome Original Research, Review, Mini Review, Methods, Perspective, and Clinical articles addressing, but not limited to, the following themes:- Age-related remodelling of neutrophil phenotype, heterogeneity, and lifespan- Neutrophil recruitment and infiltration across the blood-brain barrier and meninges- Neutrophil mediators and granule proteins in CNS pathology, including interactions with amyloid beta, RAGE signalling, microglia, astrocytes, and the neurovascular unit- Neutrophil contributions to specific age-related CNS disorders, including Alzheimer’s disease, Parkinson’s disease, ALS, and vascular cognitive impairment- NETs and neutrophil-derived biomarkers of disease onset, progression, or treatment response- Therapeutic targeting of neutrophil pathways, including NET formation and immunometabolism, with safety considerations in older adults- Methodological advances in neutrophil phenotyping and functional analysis in CNS tissue-----Topic Editor Dr. Kasus-Jacobi is the founder and owner of Alzarrok Bio and receives research funding from the National Institute on Aging and received a local award from OKBioStart. Topic Editor Dr. Pereira is the scientific founder of a university start up biotechnology company, Biolytx Pharmaceuticals Corp. All IP developed at the University of Oklahoma is licensed to Biolytx. Dr. Pereira has equity in the company but does not receive any financial compensation. Topic editors: Anne Kasus-Jacobi, Heloise Anne Pereira Source: https://www.frontiersin.org/research-topics/78780/neutrophils-from-immune-sentinels-to-agents-of-neurodegenerative-diseases-in-the-aging-cns