Background
It is widely accepted that cognitive and memory deficits in Alzheimer's disease (AD) primarily result from synaptic failure. However, the mechanisms that underlie synaptic and cognitive dysfunction remain unclear.
Methods
We utilized molecular biology techniques, electrophysiological recordings, fluorescence in situ hybridization (FISH), immuno- and Golgi-staining, chromatin immunoprecipitation (CHIP); lentivirus (LV)-based microRNA overexpression and 'sponging', and behavioral tests to assess upregulated miR-30b causing synaptic and cognitive declines in APP transgenic (TG) mice. Findings: We provide evidence that expression of miR-30b, which targets molecules important for maintaining synaptic integrity, including ephrin type-B receptor 2 (ephB2), sirtuin1 (sirt1), and glutamate ionotropic receptor AMPA type subunit 2 (GluA2), is robustly upregulated in the brains of both AD patients and APP transgenic (TG) mice, an animal model of AD, while expression of its targets is significantly downregulated. Overexpression of miR-30b in the hippocampus of normal wild-type (WT) mice impairs synaptic and cognitive functions, mimicking those seen in TG mice. Conversely, knockdown of endogenous miR-30b in TG mice prevents synaptic and cognitive decline. We further observed that expression of miR-30b is upregulated by proinflammatory cytokines and Aβ42 through NF-κB signaling. Interpretation: Our