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

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.

Grant Number: 5R01AG078892-04
NIH Institute/Center: NIH
Principal Investigator: Jayakrishna Ambati