IDENTIFICATION OF NLRP1 MEDIATED REGULATION OF MICROGLIAL IMMUNE METABOLISM IN AGEING AND NEURODEGENERATION USING PATIENT-DERIVED MICROGLIA

Ageing and neurodegeneration are closely associated with alterations in microglial immune metabolism and inflammasome signaling. This project focuses on elucidating the role of the NLRP1 inflammasome in regulating microglial immune responses in these contexts. Using human macrophage and Alzheimer’s patient-derived microglial models, we investigate how NLRP1 activation influences inflammatory signaling and metabolic function. We employ both pharmacological activation using known NLRP1 agonists and disease-relevant stimuli such as amyloid-β and tau to assess downstream effects. In addition to monitoring canonical inflammasome markers and cytokine release, we want to investigate in these in-vitro models, how NLRP1-mediated gene regulation influences microglial transcriptomes and microglial function, which are key for maintaining synaptic integrity and neuronal plasticity. Since microglial senescence has been found to cause tau pathology, a major phenotype of the aging and degenerating brain, we will further study, how NLRP1 affects microglial senescence and renewal in the respective models. Additionally, to further dissect the role of NLRP1, we have developed a CRISPR-Cas9 NLRP1 knockout model in patient-derived microglia to assess transcriptomic changes, functional alterations, and impacts on senescence and cellular renewal. This comprehensive approach aims to establish the mechanistic link between NLRP1 signaling and microglial dysregulation in neurodegenerative diseases.