Dicer1 promotes Aβ clearance via blocking B2 RNA-mediated repression of apolipoprotein E.

Metabolism of β-amyloid is critical for healthy brain. Decreased clearance of β-amyloid is associated with ensued accumulation of amyloid peptide, culminating in formation of senile plaques, a neuropathological hallmark of Alzheimer's disease(AD). Apolipoprotein E (APOE), a lipoprotein for phospholipid and cholesterol metabolism, is predominantly synthesized by glia in the central nervous system, controlling Aβ aggregation and metabolism. By use of stereotactic injection and a Morris water maze, we found that delivery of Dicer1-expressing adenovirus into the hippocampus of an animal model of AD mice APPswe/PSEN1deltaE9 significantly improved spatial memory. The effect was associated with reduced amyloid peptides in the hippocampus which were analyzed with immunofluorescence and enzyme-linked immunosorbent assay. With western blot, quantitative real-time PCR, fluorescence in situ hybridization, and northern blot,Dicer1 overexpression increased apolipoprotein E (APOE) and concomitantly decreased B2 RNA in the hippocampus of the AD mice and in astrocyte cultures whereas transfection of B2 Mm2 RNA decreased APOE mRNA and protein levels in astrocyte cultures. Further, human or mouse APOE mRNA was found containing Alu RNA or its equivalent, B2 Mm2 RNA, locating downstream of its 3'-untranslated region (UTR), respectively. The 3'-UTR or 3'-UTR in conjunction with the downstream Alu/B2 RNA were cloned into a luciferase reporter; with dual-luciferase assay, we found that simultaneous transfection of Dicer1 siRNA or Alu/B2 RNA decreased the corresponding luciferase activities which suggest that Alu RNA mediated APOE mRNA degradation. Altogether, Dicer1 expression mediated amyloid peptide clearance by increasing APOE via blocking B2 RNA-mediated APOE mRNA degradation.