Defining the role of SINE retrotransposons and inflammasome activation in Alzheimer's disease

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PROJECT SUMMARY Pathological hallmarks of Alzheimer's disease (AD) include deposition of Amyloid-β (Aβ) plaques and accumulation of hyperphosphorylated Tau aggregates in neurofibrillary tangles. These aggregates have been demonstrated to activate inflammasome signaling. Inflammasomes are innate immune platforms implicated in numerous chronic neurodegenerative and inflammatory conditions such as AD. Inflammasome inhibition is being explored as a therapeutic strategy for AD and other complex neuroinflammatory/degenerative disorders including Parkinson's disease, multiple sclerosis, and age-related macular degeneration (AMD). Recent studies have identified links between dysregulation of transposable elements (TEs) and AD. We have established a critical mechanistic role for activity of one class of TEs – short interspersed elements (SINEs) – in the pathogenesis of AMD. We have demonstrated that SINE RNA accumulation induces cellular degeneration in AMD by dual activation of the NLRP3 and NLRC4 inflammasomes. Furthermore, we have identified DDX17, an RNA helicase, as the molecular sensor of SINE RNAs that licenses dual activation of the inflammasomes. Moreover, our preliminary studies have identified dysregulation of SINE RNAs in spatial proximity to Aβ deposits in the 5xFAD model of AD and that a novel small molecule inhibitor of NLRC4-NLRP3 signaling suppresses inflammasome activation induced by Aβ aggregates. Notwithstanding these findings, major gaps in knowledge about SINE RNAs and inflammasomes in AD persist, e.g, the cellular sources of SINE RNAs in AD are undefined and whether SINE RNAs interact with and activate inflammasome components in AD is unknown. This proposal will test the hypothesis that AD pathology is exacerbated by NLRP3/NLRC4 activation induced by endogenous SINE RNA accumulation. We will test this hypothesis via three specific aims: 1) We will quantitate SINE RNA expression and inflammasome activation and map their cellular origins in the 5xFAD model of AD; 2) We will determine the cellular mechanisms of SINE RNA- induced inflammasome activation in brain microglia, whether SINE RNA compromises Aβ phagocytosis by microglia, and whether inflammasome inhibitors improve Aβ phagocytosis; and 3) We will test the effects of individual and dual inflammasome inhibitors on Aβ clearance as well as cognitive and behavioral deficits in the 5xFAD model. Collectively, these thematically related but independent aims will shed light on the contribution of SINE RNAs-induced inflammasome activation in AD. This project is responsive to RFA-AG-22-021 as it will (a) define the functional roles and causal relationships between SINE RNAs and neuroinflammation; (b) define the mechanisms underpinning innate and immune responses to SINE RNAs; and (c) test therapeutic interventions interfering with SINE RNA-mediated molecular pathways. These studies will provide a deeper mechanistic understanding of the role of TEs that can serve as a foundation for future translational research.