NLRP3-dependent and -independent effects in microglial senescence

• Applicant: Dr. Christina Ising
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555645642

With more than 50 million people worldwide already affected and the expected rise in incidence, dementia is one of the important diseases in our aging society. Tauopathies, which include Alzheimer’s disease (AD), are the most common forms of dementia and are characterized by misfolded and aggregated tau proteins as well as chronic neuroinflammation. While it is generally accepted that especially AD is an age-related disease, we do not know how exactly aging contributes to the disease. One important hallmark of aging is the occurrence of senescence, a cellular state among other things marked by release of pro-inflammatory factors termed a senescence-associated secretory phenotype (SASP). Recently, increasing numbers of senescent microglia have been detected in tauopathies in humans and mouse models and removal of these cells reduced tau pathology in a tauopathy mouse model, but the underlying mechanism remains elusive. In our own preliminary work, we identified the tau protein as an inductor of microglial senescence and found that a functional NLRP3 inflammasome, a defense mechanism present in microglia, is required for senescence induction and that it contributes to SASP formation. However, inhibition of NLRP3 did reduce but not prevent the release of a SASP from microglia while blocking the transcription factor STAT3 completely abrogated the response. As both, NLRP3 as well as STAT3 inhibition are potential treatment strategies, we need a better understanding of the molecular mechanisms connecting these pathways potentially to each other and to senescence. Therefore, we will investigate the role of the NLRP3 inflammasome and STAT3 in microglial senescence in tauopathies in more detail. First, we will generate a more complete picture of microglial senescence and especially SASP formation after blocking either NLRP3 or STAT3. Second, we will analyze the effect of STAT3 inhibition in a tauopathy mouse model with a focus on the occurrence of microglial senescence and generation of a SASP. Last, we will explore the contribution of specifically microglia ageing to the development of senescent microglia and progression of tauopathies by also taking into account NLRP3 inflammasome activation and STAT3 signaling. Taken together, this study will provide us with valuable insights into the regulation of the SASP in microglia and will help us to understand if and how NLRP3 and STAT3 may interact in this cellular state. As both, NLRP3 as well as STAT3 inhibitors are in clinical trials or even already used to treat patients with other diseases, our work will support the decision if one of these inhibitors could be a potential treatment strategy also for AD and other tauopathy patients.

• DFG Programme: Research Grants