Neutrophils and NETosis in Alzheimer’s disease: Unraveling pathogenic mechanisms and novel therapeutic targets

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system that causes cognitive decline, memory loss, and neuropsychiatric symptoms. The condition is characterized by the buildup of β-amyloid plaques (Aβ), neurofibrillary tangles (NFTs), and persistent neuroinflammation. Despite ongoing research, current therapeutic strategies remain palliative and fail to halt or reverse disease progression, underscoring the need for novel treatment approaches. Recent evidence highlights neutrophils, the most abundant blood cells, as key contributors to AD pathology. These cells cross the blood-brain barrier (BBB) via specific molecular pathways and accumulate in brain regions such as the cortex and hippocampus, particularly near Aβ plaques and NFTs. Once in the brain, neutrophils release reactive oxygen species (ROS), generate neutrophil extracellular traps (NETs) via NETosis, and secrete proinflammatory cytokines and granule components. This cascade contributes to BBB disruption, increased Aβ deposition, glial activation, chronic inflammation, neurodegeneration, and cognitive impairment in AD. This review highlights the molecular mechanisms underlying both lytic and non-lytic NET formation (NETosis), explores peripheral neutrophil alterations and their migration pathways across the BBB, and discusses the role of intracerebral neutrophils, NETs, and NETosis in AD pathophysiology. Finally, we explore emerging therapeutic strategies targeting NETs, neutrophils, and NETosis as potential disease-modifying approaches in AD. • Peripheral neutrophil alterations are linked to AD pathogenesis and progression. • Neutrophils cross the BBB and accumulate near Aβ and NFTs in AD-affected brain areas. • Neutrophils in the brain produce NETs, ROS, and cytokines, exacerbating AD pathology. • Neutrophils disrupt BBB, activate glia, and worsen neurodegeneration and memory in AD. • Therapeutic approaches targeting neutrophils and NETs offer hope for AD treatment.