Differential adenosine to inosine RNA editing of SINE B2 non-coding RNAs in mouse unveils a novel type of epi-transcriptome response to amyloid beta neuro-toxicity

Alzheimer's disease (AD) is characterized by early molecular responses to amyloid beta neuro-toxicity that remain poorly defined. RNA editing by adenosine-to-inosine (A-to-I) conversion is a major epitranscriptomic mechanism, yet its contribution to non-coding RNA regulation during neurodegeneration is largely unknown. Short Interspersed Nuclear Element (SINE)-derived RNAs, including mouse B2 RNAs, represent the dominant substrates of A-to-I editing and have recently been shown to regulate gene expression through ribozyme-mediated processing. Here, we introduce and validate a repeat-aware bioinformatics framework that enables position-specific quantification of A-to-I editing within highly repetitive SINE RNAs - an analysis that has been challenging using standard genome-based pipelines. Applying this approach, we uncover discrete editing hotspots in B2 RNAs whose modification is selectively increased during the earliest stages of amyloid beta pathology. Elevated B2 RNA editing is consistently observed in hippocampal neurons exposed to acute amyloid beta toxicity. Functional perturbation of ADAR activity alters both B2 RNA editing levels and expression of B2 RNA-regulated stress response genes, directly linking RNA editing to SINE-mediated transcriptional control. Independent validation using Nanopore direct RNA sequencing supports increased RNA modification signals at the same B2 RNA regions identified by short-read Illumina sequencing. Together, our findings establish a previously unrecognized epitranscriptomic response to amyloid beta neurotoxicity mediated by site-specific A-to-I editing of SINE RNAs. This work defines a new analytical paradigm for studying RNA editing in RNAs from repetitive elements and reveals a regulatory axis connecting amyloid beta toxicity, ADAR activity, SINE RNA editing, and stress-responsive gene expression, with implications for conserved mechanisms underlying Alzheimer's disease and related neurodegenerative disorders.