Neuroinflammation

Neuroinflammation is when your brain's innate immune system, mainly microglia and astrocytes, gets activated, by protein clumps, injury, or the sterile signals of aging. It produces a sustained release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and reactive oxygen species. Short-term, this is protective. But with age, it turns chronic and harmful. Microglia shift from calm surveillance to a pro-inflammatory state, and they clear amyloid-β less well; astrocytes turn 'reactive' (gliosis). A central hub is the NLRP3 inflammasome. Amyloid-β clumps and tau aggregates activate it, which triggers caspase-1 and the release of IL-1β. Ising et al. (2019, Nature) showed that knocking out NLRP3 in a tau mouse model reduced tau over-phosphorylation and improved cognition; NLRP3 was also active in microglia from frontotemporal-dementia brains. Heneka et al. (2015, Lancet Neurology) established neuroinflammation as a third hallmark of Alzheimer's, with raised IL-1β, TNF-α, and IL-6 in patients' spinal fluid and blood. Ransohoff (2016, Science) framed a triad: microglial activation, cytokine release, and synaptic injury, where protective players become drivers of neurodegeneration when they stay switched on. Genetic risk converges here too: TREM2 loss-of-function variants impair the cleanup, and APOE4 biases microglia toward inflammation. Whether neuroinflammation comes before Alzheimer's pathology or reacts to it is still contested. NSAID trials failed, and NLRP3 inhibitors work only in early preclinical models as of 2026.

Last reviewed: June 22, 2026

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