Investigating retrotransposon-derived products as a source of tau-mediated neuroinflammation

Tauopathies are a group of devastating and incurable age-related neurodegenerative disorders that are neuropathologically defined by toxic species of the protein tau. Therapies directly targeting tau have been largely ineffective, and it is therefore essential that we develop a better understanding of the downstream mechanisms of tau that may be directly driving neurotoxicity. A recently discovered causal mediator of toxicity in tauopathies is the activation of retrotransposable elements (RTEs). Tau causes RTEs to become aberrantly expressed in neurons and have been previously shown to drive neuroinflammation via activation of the innate immune system. Additionally, a new key mediator of neuroinflammation in tau pathology is the NLRP3 inflammasome. Studies have demonstrated that RTE-mediated neuroinflammation can be suppressed by repurposing NRTIs, a class of drugs used to treat retroviral infections such as HIV. The NLRP3 inflammasome is also inhibited by NRTIs. Despite this, the effects of NRTIs in settings of tauopathy remain insufficiently characterized. I will draw on years of molecular biology experience in my sponsor’s laboratory to further our understanding of RTE activation in the context of tauopathies. In other disease contexts, aberrantly expressed RTEs are released from cells. Given the neuroinflammatory sequela of RTEs, it is essential to determine if neurons also release RTEs, as this will likely unveil new therapeutic approaches for tauopathies. Additionally, inhibition of the NLPR3 inflammasome by NRTIs in the context of tauopathy has never been studied. Based on this, I hypothesize that NRTIs reduce tau-mediated neuroinflammation by inhibiting RTE expression-driven inflammasome activation. To test this hypothesis, I will examine the consequences of RTE activation by combining advanced modelling of human-derived iPSCs with molecular biology techniques. In Aim 1, I will identify which RTE products are elevated by pathogenic tau and determine if they are secreted by neurons by using confocal microscopy and western blotting. In Aim 2, I will characterize the effects of NRTIs on RTE-mediated activation of the innate immune system through cellular viability assays and culturing microglia and astrocytes in media derived from pathogenic tau-affected neurons. My long-term goal for this award is to transition into a career as a physician-scientist studying and treating age-related neurodegeneration. The sponsor team will share their expertise in molecular biology research, clinical evaluations, and career development. Further training will be acquired from workshops and conferences, both at and outside of Brown University, in addition to national and international conferences. Overall, this proposal will provide research and clinical training in addition to professional development. Project Number: 1F30AG101976-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Zachary Uttke | Institution: BROWN UNIVERSITY, PROVIDENCE, RI | Award Amount: $55,114 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F03C-F (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11388271