circAβ-a RNA encoded Aβ175—the hidden driver of β-amyloid plaque formation and deposition in sporadic Alzheimer’s disease

Mechanisms that trigger Aβ production in sporadic Alzheimer’s disease are still obscure. We recently reported the expression of a human circular RNA (circAβ-a) encoded Aβ peptide precursor variant (Aβ175). Presently, we demonstrated that AAV9 virus-expressed circAβ-a gave rise to extensive extracellular Aβ plaque depositions and microglial activation in mouse brain; this recapitulates critical pathogenic hallmarks within a sporadic AD mouse model. Specifically developed antibodies detected robust endogenous Aβ175 expression in HEK293 cells and hNSC-derived human neurons, underscoring the potential of Aβ175 as a salient Aβ precursor. Furthermore, we detected high levels of Aβ175 oligomers in young-adult human brains. In intermediate and old-age human brain samples, accumulation of soluble Aβ175 pentamers was reduced and Aβ175 oligomers were components of most insoluble Aβ plaques in older human brain. We propose a causal relationship between human circAβ-a RNA expression, dysregulation of Aβ175 oligomer processing/aggregation and Aβ plaque accumulation in sporadic AD.