Clémence Tropis; Janna Jernigan Posey; Malú Gámez Tansey; Michael T. Heneka · 2026 · Molecular Neurodegeneration
Paper
Abstract As life expectancy increases worldwide, the proportion of people aged 65 and older is expected to double by 2050 and these global demographic shifts will be accompanied by an increase in age-related neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). AD is the leading cause of dementia worldwide, characterized by progressive cognitive decline linked to amyloid beta accumulation, tau pathology, neuronal cell death and chronic neuroinflammation. PD is the most common movement disorder worldwide, characterized by progressive motor decline linked to alpha-synuclein accumulation, formation of Lewy bodies and neurites, dopaminergic neuron death, as well as chronic neuroinflammation. Increasing evidence implicates inflammasomes, intracellular multiprotein complexes that orchestrate innate immune responses, as key drivers of the neuroinflammatory milieu in AD and PD. The NLRP3 inflammasome, mostly expressed by microglia, has been shown to activate caspase-1, resulting in the cleavage and release of pro-inflammatory cytokines IL-1β and IL-18 and promoting pyroptotic cell death within the central nervous system. This review synthesizes current knowledge on the molecular mechanisms of inflammasome activation, their pathological involvement in AD and PD, and the genetic underpinnings supporting their role. It further highlights emerging therapeutic strategies aimed at modulating inflammasome activity, evaluating preclinical outcomes and clinical trial progress. Understanding inflammasome dynamics provides critical insight into AD and PD pathophysiology and presents promising targets for future disease-modifying treatments.
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