NLRP3-Mediated Glutaminolysis Regulates Microglia in Alzheimer's Disease

Abstract

Activation of the NLRP3 inflammasome has a key role in the progression of Alzheimer’s disease (AD), via the characterised release of IL-1β and ASC specks. However, whether NLRP3 was involved in pathways beyond this remained unknown. Here we show that loss of NLRP3 influences glutamine/glutamate-related metabolism, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function including more significant phagocytosis of Aβ peptides. This pathway is conserved between mouse and man. Critically, we can mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, this data demonstrates a new role for the NLRP3 inflammasome, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD..

Funding Information: Alzheimer Forschung Initiative grant #20043 (RMM) Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048 (RMM, EL, MTH) European Union Joint Programme– Neurodegenerative Disease (JPND) consortium InCure (funding code 01ED1505A) (MTH, JT) Helmholtz Association, under the project title 'Immunology&Inflammation', #ZT-0027 (MTH and EL) HOMEO-HIRN: Neuronale Kompartimente im Zusammenspiel von Krankheit und Gesundheit # ZN3673 (KH) Declaration of interes

Declaration of Interests: MTH: Clinical advisory board member at IFM Therapeutics, scientific advisory board member at Alector, associate editor of Neurology and Neuroinflammation, Honoraria for oral presentations from Pfizer, Novartis, Roche, Abbvie and Biogen. EL: Co-founder and adviser at IFM Therapeutics All other authors declare that they have no competing interests

Ethics Approval Statement: Animal care and handling was performed as approved by the local ethical committees.The ethical approval statement has been included in the text, the approval was issued by the local/federal authority LANUV (Landesamt für Natur, Umwelt und Verbraucherschutz NRW), the respective approval numbers are:
81-02.04.2019.A026 and 81-02.04.2020.A221. The human samples used in this study were purchased from the Banner Health Collection, and therefore don't require additional ethical approval, according to our information.

Keywords: Microglia, Alzheimer's disease, NLRP3, inflammasome, glutaminolysis, α-ketoglutarate, phagocytosis, amyloid-β