Neuroinflammation

Neuroinflammation is activation of the brain's innate immune system — principally microglia and astrocytes — by protein aggregates, injury, or sterile aging signals, producing sustained release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and reactive oxygen species. Acutely protective, this response becomes chronic and maladaptive with aging. Microglia shift from homeostatic surveillance to pro-inflammatory activation, losing phagocytic efficiency for amyloid-β clearance; astrocytes undergo reactive gliosis. The NLRP3 inflammasome is a central node: amyloid-β oligomers and tau aggregates activate this cytosolic complex, triggering caspase-1 cleavage and IL-1β secretion. Ising et al. (2019, Nature) showed NLRP3 knockout in a tau mouse model reduced hyperphosphorylation and improved cognition; NLRP3 was activated in post-mortem frontotemporal dementia microglia. Heneka et al. (2015, Lancet Neurology) established neuroinflammation as a third hallmark of Alzheimer's disease, with CSF and serum elevations of IL-1β, TNF-α, and IL-6 in AD patients. Ransohoff (2016, Science) framed the triad: microglial activation, cytokine release, and synaptic injury — protective mediators becoming drivers of neurodegeneration when sustained. Genetic risk converges: TREM2 loss-of-function variants impair phagocytosis; APOE4 biases microglia toward pro-inflammatory states. Whether neuroinflammation causally precedes Alzheimer pathology or is reactive remains contested; NSAID trials failed, and NLRP3 inhibitors show efficacy only in early preclinical models as of 2026.