NLRP3 regulates microglial metabolic function in Alzheimer's disease. (20th December 2022)

• Record Type: Journal Article
• Authors: McManus, Roisin M.; Komes, Max P; Griep, Angelika; Santarelli, Francesco; Schwartz, Stephanie; Khalil, Michelle‐Amirah; Lauterbach, Mario; Gomez‐Cabrero, David; Tegner, Jesper; Hiller, Karsten; Latz, Eicke; Heneka, Michael T.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.065598
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Our laboratory has demonstrated that the NLRP3 inflammasome has a critical part in the microglial innate immune response to Alzheimer's disease (AD)‐related peptides, triggering the production of cleaved‐caspase‐1 and IL‐1β. NLRP3 activation was found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic mouse models of AD expressing amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology and neuroinflammation. Here, we set out to determine the genes and pathways under the influence of NLRP3, beyond the established release of IL‐1β and ASC that could be contributing to the progression of AD. Method: Single cell RNA sequencing was performed on CD11b + cells from the brains of aged wildtype, APP/PS1, NLRP3 −/− and APP/PS1.NLRP3 −/− mice. Microglia were prepared from the brains of 1‐day old wildtype and NLRP3 −/− mice to assess real‐time metabolic function, phagocytosis assays and flow cytometric analysis. Targets were investigated in the post‐mortem brain tissue of those with and without AD. In a separate series of experiments, microglial cells and APP/PS1 mice were treated with novel NLRP3‐targeted inhibitors to confirm findings. Result: Single cell RNA sequencing analysis found a unique cluster of microglia with pathways related to phagocytosis and glutamate metabolic signaling in APP/PS1.NLRP3 −/− mice. Metabolic analysis found that NLRP3 −/− microglia had enhanced mitochondrial and metabolic function. NLRP3 −/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with cellular utilization of glutamate and glutamine. Importantly, we were able to replicate these findings in human cells and using NLRP3‐specific inhibitors in vitro and in vivo . Conclusion: We have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate‐related metabolism, which was associated with enhanced phagocytic activity. This pathway is conserved between mouse and man. Critically, we can mimic this effect pharmacologically using NLRP3‐specific inhibitors. Together, our data strengthens NLRP3 as a master‐immune regulator and an important target in the treatment of AD and dementia.