Dicer1 is a microRNA-processing enzyme which plays critical roles in neuronal survival and neuritogenesis. Dicer1 deletion induces neurodegeneration or degeneration in retinal pigment epithelium, which is associated with oxidative stress. Oxidative stress is thought to be central in the pathogenesis of Alzheimer's disease (AD). Therefore, we hypothesize that Dicer1 may play roles in AD. Using immunoblotting and quantitative real-time PCR, Dicer1 protein and mRNA were reduced in the hippocampi of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-mediated Dicer1 knockdown induced oxidative stress and apoptosis and reduced mitochondrial membrane potential in cultured neurons. Chronic Aβ42 exposure decreased Dicer1 and nuclear factor erythroid 2-related factor 2 (Nrf2) which were reversed by N-acetyl-cystein. Nrf2 overexpression increased Dicer1 mRNA and protein and reverted the Aβ42-induced Dicer1 reduction. We further cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Notably, injection of Dicer1-expressing adenovirus into the hippocampus of the mice significantly improved spatial learning. Altogether, we found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. These results suggest that Dicer1 is a target in AD therapy, especially at the early stage of this disorder. In this study, we found that Dicer1 was reduced in the brain of AD mice which is the first report to examine Dicer1 in AD. We further found (i) that Aβ42 exposure decreased Dicer1 via attenuating Nrf2-ARE signaling and (ii) injection of Dicer1-expressing adenovirus into the hippocampus of the AD mice significantly improved spatial learning. Altogether, we found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. This study may open new avenues for investigating potential pathognomonics and pathogenesis in AD.
