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.
Highlights
Alzheimer’s disease (AD) is one of the most common and devastating forms of dementia
For the detection of circAβ-a in various human brain samples, we performed RT-PCR with two pairs of divergent primers
Reverse primer circAβ-a-R1 mapped to the splice junction region of circAβ-a; this design ensured the specificity of our PCR reaction (Figure 1A)
Summary
Alzheimer’s disease (AD) is one of the most common and devastating forms of dementia. Several mutations within the CDS (protein coding sequence) of APP were identified and the specific association of these genetic variants with increased accumulation of Aβ were established [12,15,16,17,18,19,20,21,22,23]. The most common form of AD is the “sporadic” variant This specific form of AD prevails in patients aged 65 or older and unlike familial AD, no specific mutations in APP and presenilin genes were identified. Apart from these striking genetic differences, both forms are characterized by the overproduction of Aβ plaques in the brain [2,11,12,14,35,36]. C-terminus translated out-of-frame that the canonical mRNA could not have generated
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