A novel mechanism of synaptic and cognitive impairments mediated via microRNA-30b in Alzheimer's diseaseResearch in context

Abstract

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 results provide a previously undefined mechanism by which unregulated miR-30b causes synaptic and cognitive dysfunction in AD, suggesting that reversal of dysregulated miR-30b in the brain may prevent or slow cognitive declines in AD. Fund: This work was supported by National Institutes of Health grants R01NS076815, R01MH113535, R01AG058621, P30GM103340 Pilot Project, and by the LSUHSC School of Medicine Research Enhancement Program grant (to C.C.). Keywords: Alzheimer's disease, Synaptic failure, Dementia, Small noncoding RNA, miRNA sponge, Neuroinflammation, Nuclear factor kappa B