Scientists from the German Center for Neurodegenerative Diseases (DZNE), the University of Bonn, and the University Hospital Bonn (UKB) have uncovered new insights into the role of neuroinflammation in Alzheimer's disease (AD). The groundbreaking study, led by Róisín M. McManus from the McManus Lab (a member of SFB 1454), reveals that the NLRP3 inflammasome, a key player in the innate immune response, also regulates crucial aspects of microglial metabolism and their ability to clear amyloid-beta (Aβ) plaques, a hallmark of AD. The findings suggest that reducing neuroinflammation through targeted NLRP3 inhibition could offer a promising therapeutic avenue for combating this devastating disease.
Published in Immunity, the research challenges the traditional understanding of NLRP3's involvement in AD. While it was previously known that NLRP3 activation leads to the release of inflammatory cytokines and the formation of ASC specks that promote Aβ aggregation, this study demonstrates a direct link between NLRP3 and microglial metabolism.

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Key Discoveries:
- NLRP3's Metabolic Control: The study reveals that NLRP3 normally acts as a regulator of microglial metabolism.
- Boosting Glutamine Utilization: Inhibiting NLRP3 leads to increased utilization of glutamine, a key energy source for microglia, and elevates levels of α-ketoglutarate
(αKG), a critical metabolite.
- Epigenetic Reprogramming: The increased αKG levels trigger epigenetic changes within microglia, specifically promoting the transcription of genes involved in phagocytosis, the process by which microglia clear debris and Aβ plaques.
- Enhanced Aβ Clearance: This metabolic and epigenetic reprogramming significantly enhances the ability of microglia to engulf and degrade Aβ plaques.
- Pharmacological Potential: Importantly, McManus et al. demonstrated that these beneficial effects can be replicated using NLRP3-specific inhibitors. However, chronic
inhibition was necessary to achieve the desired metabolic and functional changes in microglia.
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How NLRP3 Impacts Alzheimer's Disease

In the AD brain, the deposition of Aβ triggers NLRP3 activation in microglia. This activation, however, appears to disrupt the normal metabolic function of these cells. By genetically deleting NLRP3 in a mouse model of AD, the researchers observed a boost in glutamine and glutamate metabolism, along with increased expression of the glutamate aspartate transporter Slc1a3. This metabolic shift resulted in enhanced mitochondrial activity and increased production of αKG, ultimately leading to more efficient Aβ clearance by microglia.

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The Importance of Chronic Inhibition

One of the most significant findings of the study is the realization that acute or short-term inhibition of NLRP3 is insufficient to achieve the desired therapeutic effects. The researchers discovered that only chronic NLRP3 inhibition could mimic the beneficial effects observed with genetic deletion of NLRP3. This chronic inhibition leads to a reprogramming of microglial metabolism and function, driven by αKG-mediated epigenetic changes and increased Slc1a3 expression.

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A collaborative endeavor
This project was a joint effort of the SFB 1454 „Metaflammation and Celluar Programming”, involving various laboratories. In addition to the McManus Lab, the Heneka Lab, the Latz Lab and the Hiller Lab were also key contributors. This highlights the collaborative nature of the SFB in driving forward research. Beside the SFB-researchers’ experts from the Luxembourg Centre for Systems Biomedicine, University of California San Diego, Technische Universität Braunschweig, Novartis Switzerland, and other institutions in Europe and beyond were involved.

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Original Publication:
NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s
disease progression, Immunity (2025), Róisín McManus et al., DOI: 10.1016/j.immuni.2025.01.007