NETosis in Alzheimer's Disease: Understanding the Role of Neutrophil Extracellular Traps (NETs) in Neuroinflammation and Disease Pathogenesis.

Alzheimer's disease (AD) is a common neurodegenerative disease of the elderly and the sixth leading cause of death. Various risk factors are responsible for the disease, including aging, vascular disorders, head trauma, infection, genetics, and environmental conditions. Amyloid beta (Aβ) and neurofibrillary tangle (NFT) build-up lead to the generation of free radicals, which in turn cause oxidative stress and neuroinflammation that further cause synaptic and mitochondrial dysfunction. These inflammatory responses primarily stem from the overactivation of microglial and astroglial cells, producing cytokines and chemokines. However, immune cell migration has also been observed in the central nervous system (CNS) via blood-brain barrier (BBB) disruption, in which neutrophils have grabbed more attention due to their migration and formation of neutrophil extracellular traps (NETs) in AD brain parenchyma and blood vessels, causing chronic neuroinflammation and neuronal damage via NETosis. NETosis is the immune system's defense mechanism in which neutrophils form web-like structures to trap pathogens and digest them with their antimicrobial and cytotoxic peptides and release inflammatory cytokines. Neutrophils and NETs have been observed in many studies surrounding Aβ plaques in the brain parenchyma and cerebral blood vessels, causing neuronal tissue damage and AD progression. The ongoing research advocates that by targeting conventional Aβ plaques and tau build-up, managing neuroinflammation, particularly caused by NETosis, may delay the onset or reduce its progression. In the growing health care scenario, to avoid any side effects and the cost of the present discovered drugs, the focus should be on organic or natural components/compounds for which phytochemicals will be the best to target NETosis, as they have many medicinal properties like anti-oxidant, anti-inflammatory, anti-microbial, and immunomodulatory. This review focuses on understanding the molecular association between neuroinflammation in NETs and AD progression and the role of plant-derived constituents in tackling the NETosis-induced AD progression.