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Impact of Inflammasome Deactivation on Alzheimer’s Disease

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This research proposal from the Dixit laboratory, which will be pursued in interdisciplinary collaboration with the lab of Dr. Rudy Tanzi at Massachusetts General Hospital (MGH), emanates from our original findings that NLRP3 inflammasome activation in microglia controls age-related inflammation in the central nervous system (CNS) and that CD33-dependent inhibition of amyloid-beta uptake by microglia reduces IL-1beta to protect against AD. Inflammasome is a high molecular weight protein complex that assembles in the cytosol of microglia and myeloid-lineage cells upon encounter with ‘damage-associated molecular patterns’ such as amyloids, lipotoxic fatty acids or extracellular ATP derived from necrotic cells. Upon assembly, this causes caspase-1 dependent release of pro-inflammatory cytokines IL-1beta, IL-18 and a special form of cell death called pyroptosis1.

Studies from our lab have identified that the NLRP3 inflammasome controls development of inflammation-associated degenerative diseases during aging. Consistent with our data, independent studies also have demonstrated the increased activation of NLRP3 inflammasome in AD in humans and that genetic loss of NLRP3 protects against dementia in APP/PS1 mouse model. Although it is established that inflammation plays a pivotal role in development of Alzheimer’s disease (AD), the therapeutic approaches that impact specific innate immune mechanisms in the microglia remain to be identified. Interestingly, our preliminary results show that a subset of elderly are protected from age-related inflammation and microglial activation despite the presence of amyloid-beta plaques. This implies there must be endogenous protective mechanisms that maintain homeostasis in aging by preventing the sensing of aberrant Abeta deposits in microglia resulting in reduced inflammatory damage. Therefore, the long-term goal of this proposal is to identify and harness anti-inflammasome regulators as therapeutic targets to prevent or treat AD.

This proposal is based on our discovery that ketone metabolite beta-hydroxybutyrate (BHB) and NLRP3 inflammasome constitutes an immunometabolic checkpoint of binary opposition—endogenous polar signals that work in concert to regulate the innate immune response. Ketone bodies, BHB and acetoacetate (AcAc) support mammalian survival during periods of starvation by serving as a source of ATP in tricarboxylic acid (TCA) cycle for brain function. Intriguingly, we have found that macrophages and microglia highly express the key ketogenic enzyme 3-Hydroxy-3-MethylGlutaryl-CoA Lyase (HMGCL). This suggests that microglia can produce ketone bodies and that local levels of BHB in brain may function as a regulatory metabolite that restrains the runaway inflammasome activation. In addition, this suggests that medium-chain triglycerides (MCTs), which can cross the blood-brain barrier, serve as substrates for production of BHB in microglia. Given MCTs are under investigation to lower AD severity, the mechanism of microglial-derived BHB as regulatory anti-inflammasome metabolite has high clinical impact. Thus, based on our findings, the central hypothesis of this project is that ketogenic substrate switch underlies the regulatory microglial responses that protects against AD by inhibition of CD33 and deactivation of the NLRP3 inflammasome. The corollary is that elevating CNS ketogenesis and BHB signaling may serve as an anti-inflammatory intervention against AD.