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

Abstract

BackgroundIt 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.MethodsWe 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.FindingsWe 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.InterpretationOur 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.FundThis 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.).

The Regulation of microRNAs in Alzheimer's Disease

“…In the study of AD patients, miR-34a/p73 expression is found to be remarkably increased in hippocampal tissues, which participates in modulating synaptic activity by lessening synaptotagmin-1 expression (44). Through microRNA microarray screening analysis, the significant up-regulation of miR-30b in the brain of AD patients and transgenic mice is observed (45). The overexpression of miR-30b in hippocampal tissues can jeopardize synaptic structure and function of hippocampal neurons; in turn, can cause the deficits in cognitive function in normal wild type animals.…”

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“…In a mouse model of peripheral inflammation induced by pancreatic ductal adenocarcinoma (PDAC), EVs containing miR-30 are up-regulated and abrogate tumor-suppressing mechanisms [134]. Interestingly, cerebral miR-30 directly impairs synaptic transmission and plasticity of hippocampal neurons [135]. The release of tumor-derived miR-30 into the circulation and subsequent localization to the CNS could provide an uninterrupted mechanism of tumor-induced cognitive impairment.…”

A Comprehensive Transcriptome Analysis Identifies FXN and BDNF as Novel Targets of miRNAs in Friedreich’s Ataxia Patients

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