Using a combination of DNA and miRNA array technologies, enhanced LED-Northern and Western blot hybridization, and the magnesium-dependent exoribonuclease and circRNA-sensitive probe RNaseR, researchers from Louisiana State University Health Science Center recently provided evidence of a significantly misregulated ciRS-7-miRNA-7-UBE2A circuit in sporadic Alzheimer’s disease (AD) neocortex (Brodmann A22) and hippocampal CA1. Deficits in ciRS-7-mediated “sponging events”, resulting in excess ambient miRNA-7 appear to drive the selective down-regulation in the expression of miRNA-7-sensitive mRNA targets, such as that encoding the ubiquitin conjugating enzyme E2A (UBE2A; chr Xq24). UBE2A, which normally serves as a central effector in the ubiquitin-26S proteasome system, coordinates the clearance of amyloid peptides via proteolysis, is known to be depleted in sporadic AD brain and, hence, contributes to amyloid accumulation and the formation of senile plaque deposits. Dysfunction of circRNA-miRNA-mRNA regulatory systems appears to represent another important layer of epigenetic control over pathogenic gene expression programs in the human CNS that are targeted by the sporadic AD process.
(A): up-regulated miRNA-7 in AD brain; lack of the miRNA-7 (ciRS-7) sponge by insufficient ciRS-7 suggests the miRNA-7 would be increased in the same brain regions where ciRS-7 is down-regulated as is observed; data in (A) quantified in bar graph format in (B); down-regulation of a family of miRNA-7-sensitive mRNA targets in the sporadic AD brain includes UBE2A; other mRNA targets may be involved; (C): detection of circRNA for miRNA-7 (ciRS-7) in sporadic AD and age-matched control hippocampal CA1 (control (CON) N = 4; AD (ALZ) N = 6]; (D): AD ciRS-7 is significantly reduced to ~0.18-fold of control (CON) in AD (ALZ) hippocampal CA1 (HIPP CA1), to ~0.22 of control in the superior temporal lobe (Brodmann A22; NCTX A22) but not the brain stem (BRAINSTEM); this implicates loss of miRNA-7 sponge effects, and ambient up-regulation of miRNA-7 in at least two anatomical areas targeted by the AD process.