Increased Alu RNA processing in Alzheimer brains is linked to gene expression changes.

Despite significant steps in our understanding of Alzheimer's disease (AD), many of the molecular processes underlying its pathogenesis remain largely unknown. Here, we focus on the role of non-coding RNAs produced by small interspersed nuclear elements (SINEs). RNAs from SINE B2 repeats in mouse and SINE Alu repeats in humans, long regarded as "junk" DNA, control gene expression by binding RNA polymerase II and suppressing transcription. They also possess self-cleaving activity that is accelerated through their interaction with certain proteins disabling this suppression. Here, we show that similar to mouse SINE RNAs, human Alu RNAs, are processed, and the processing rate is increased in brains of AD patients. This increased processing correlates with the activation of genes up-regulated in AD patients, while increased intact Alu RNA levels correlate with down-regulated gene expression in AD. In vitro assays show that processing of Alu RNAs is accelerated by HSF1. Overall, our data show that RNAs from SINE elements in the human brain show a similar pattern of deregulation during amyloid beta pathology as in mouse.

Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology.

The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer's disease (AD).