Circular RNAs (
circRNAs) have gained growing attention in participating in various biological processes and referring to multiply kinds of diseases. Although differentially expressed
circRNA profiling in
Alzheimer's disease (AD) has been established, little is known about the precise characteristic and functions of key
circRNAs with direct relevance to AD in gene expression and disease-related cognition. Herein, we screened and identified circCwc27 as a novel
circRNA implicated in AD. CircCwc27 was a neuronal-enriched
circRNA that abundantly expressed in the brain and significantly upregulated in AD mice and patients. Knockdown of circCwc27 markedly improved AD-related pathological traits and ameliorated
cognitive dysfunctions. Mechanistically, we excluded the
miRNA decoy mechanism and focused on the important function of
circRNA-
RNA-binding protein (RBP) interaction in AD. CircCwc27 directly bound to
purine-rich
element-
binding protein A (Pur-α), increased retention of cytoplasmic Pur-α, and suppressed Pur-α recruitment to the promoters of a cluster of AD genes, including
amyloid precursor
protein (APP),
dopamine receptor D1 (Drd1),
protein phosphatase 1, regulatory inhibitor subunit1B (Ppp1r1b),
neurotrophic tyrosine kinase, receptor, type 1 (Ntrk1), and LIM homeobox 8 (Lhx8). Downregulation of circCwc27 enhanced the affinity of Pur-α binding to these promoters, leading to altered transcription of Pur-α targets. Moreover, Pur-α overexpression largely phenocopied circCwc27 knockdown in preventing Aβ deposition and
cognitive decline. Together, our findings suggest significant functional consequences of a
circRNA-
protein interaction, that circCwc27, by associating with the regulatory
protein Pur-α, may act as a crucial player in AD pathogenesis and represent a promising AD therapeutic target with clinical translational potential.