Our understanding of the highly specialized functions for small non-coding 
single-stranded RNA (ssRNA) in the transcriptome of the human central nervous 
system (CNS) continues to evolve. Circular RNAs (circRNAs), a recently 
discovered class of ssRNA enriched in the brain and retina, are extremely stable 
and intrinsically resilient to degradation by exonuclease. Conventional methods 
of ssRNA, microRNA (miRNA), or messenger RNA (mRNA) detection and quantitation 
requiring free ribonucleotide ends may have considerably underestimated the 
quantity and significance of CNS circRNA in the CNS. Highly-specific small 
ssRNAs, such as the ~23 nucleotide (nt) Homo sapien microRNA-7 (hsa-miRNA-7; chr 
9q21.32), are not only abundant in the human limbic system but are, in addition, 
associated with a ~1400 nt circRNA for miRNA-7 (ciRS-7) in the same anatomical 
region. Structurally, ciRS-7 contains about ~70 tandem anti-miRNA-7 sequences 
and acts as an endogenous, anti-complementary miRNA-7 "sponge" that attracts, 
binds, and, hence, quenches, natural miRNA-7 functions. 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, here we provide 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.