Circular RNA Encoded Amyloid Beta peptides—A Novel Putative Player in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides—a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates.

A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer’s disease patients

“…circRNAs can regulated protein expression and function by interacting with the protein or through protein complex (72). Another described function of circRNAs is the ability to translate into proteins as some of them have internal ribosomal entry site (IRES) within their sequences (32). circRNAs may also act as miRNAs sponges disrupting its function as inhibitors of mRNAs (28,73).…”

“…In addition, APP and MAPT are genes encoding the main proteins involved in AD, i.e. amyloid precursor protein and tau protein, which circRNAs are also transcribed from (31,32). Most interestingly, A peptides may be synthesized from an APP-derived circRNA, known as circA-a (32,33).…”

The Emerging Role of Circular RNAs in Alzheimer’s Disease and Parkinson’s Disease

“…The potential of circRNA as a biomarker for AD has been previously demonstrated in small-scale clinical studies. For example, Mo et al ( 2020 ) suggested that circAβ-A (hsa_circ_0007556) was a promising therapeutic target in both cultured cells and brains of AD patients. Compared with traditional biomarkers for AD, circRNA has the following advantages: (i) circRNA is highly expressed in the brain—higher than in other tissues and organs—and is tissue-specific (Rybak-Wolf et al, 2015 ); (ii) the circular structure of circRNA is more stable than that of linear RNA and is resistant to enzyme digestion (Verduci et al, 2019 ); and (iii) circRNAs are transferred as exosomes from the brain to bodily fluids, thus making it easier to detect them and avoiding interference from various enzymes and humoral factors (Greene et al, 2017 ).…”

riboCIRC: a comprehensive database of translatable circRNAs

“…Furthermore, by performing in vivo and in vitro translation assays, circRNAs have been shown to enable cap-independent translation and generate functional proteins. Of these proteins, some have been demonstrated to play vital roles under a number of pathophysiological conditions, such as muscle-enriched circRNA circ-ZNF609 [ 10 ] and brain-ubiquitously expressed circRNA circAβ-a [ 15 ]. In addition, several mechanisms for circRNA translation have been proposed.…”