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bioRxiv · 10.1101/2022.08.07.503077

circAβ RNA drives the formation and deposition of β-amyloid plaques in the sporadic Alzheimer's disease

Mo, D.
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Abstract

{beta}-amyloid peptides (A{beta}) play key causal role in Alzheimers disease (AD). However, the mechanisms of A{beta} biogenesis in sporadic AD are still largely unknown. Moreover, current AD mouse models which overexpress mutated human APP and presenilin proteins can only mimic limited characteristics of familial AD. We recently discovered an alternative A{beta} production pathway from A{beta}175, an A{beta} peptide containing polypeptide translated from circular circA{beta}-a RNA generated via backsplicing of the APP gene transcript. Here, wildtype human circA{beta}-a RNA was overexpressed in wildtype mouse frontal cortex. Results showed that circA{beta}-a overexpression drove intracellular A{beta} accumulation and extensive depositions of neuronal A{beta} plaques in mouse brain in vivo. This recapitulates the critical A{beta} hallmarks of sporadic AD and represents a sporadic AD mouse model. In summary, the causal relationship between circA{beta} RNA overexpression and AD pathology was demonstrated. This novel AD mouse model will accelerate disease-modifying drug development of this detrimental neurodegenerative disease.

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Mo, D.. 2022-08-07. circAβ RNA drives the formation and deposition of β-amyloid plaques in the sporadic Alzheimer's disease. https://doi.org/10.1101/2022.08.07.503077

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