Inhibition of neuronal DICER–miR-34a/346 signaling attenuates amyloid pathology in 5×FAD mice

MicroRNAs (miRNAs) are critical regulators of genes underlying Alzheimer’s disease (AD) pathogenesis, yet the role of neuronal DICER, a key ribonuclease essential for miRNA maturation, remains unclear. While biochemical analysis of human postmortem cortical tissues revealed upregulation of DICER in AD, re-analysis of a single-nucleus RNA-sequencing (snRNA-seq) dataset confirmed elevation of DICER1 transcript in excitatory neurons of AD brains. Using a combination of integrated miRNA-seq, gene knockout (KO) and overexpression, luciferase reporter assay, and actinomycin D assay techniques, we identified miR-34a and miR-346 as the key downstream mediators of DICER that regulate APP mRNA stability through binding to the APP 3′ and 5′ untranslated regions, respectively. To uncover the role of DICER in amyloid deposition, we generated neuron-specific Dicer conditional KO (cKO) mice in the 5×FAD background. Dicer cKO/5×FAD mice exhibited significantly reduced plaque burden in the cortex. To verify the importance of miR-34a/346 in DICER-dependent APP expression, miR-34a/346 antagomirs were injected into 5×FAD brains. While antagomir-treated 5×FAD mice exhibited reduced plaque burden and neuroinflammation, they displayed improved cognitive functions. Collectively, these findings identify neuronal miR-34a/346 as critical regulators of cerebral amyloid pathogenesis and as potential therapeutic targets for AD.