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Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer's disease.

ABSTRACT: Abnormal accumulation of ?-amyloid (A?) is the major neuropathological hallmark of Alzheimer's disease (AD). However, the mechanisms underlying aberrant A? formation in AD remain unclear. We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces A? by inhibiting ?-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for A? formation. However, the molecular mechanisms responsible for suppression of BACE1 by inhibition of 2-AG metabolism are largely unknown. We demonstrate here that expression of the noncoding small RNA miR-188-3p that targets BACE1 was significantly downregulated both in the brains of AD humans and APP transgenic (TG) mice, a mouse model of AD. The downregulated miR-188-3p expression was restored by MAGL inhibition. Overexpression of miR-188-3p in the hippocampus reduced BACE1, A?, and neuroinflammation and prevented deteriorations in hippocampal basal synaptic transmission, long-term potentiation, spatial learning, and memory in TG mice. 2-AG-induced suppression of BACE1 was prevented by miR-188-3p loss of function. Moreover, miR-188-3p expression was upregulated by 2-AG or peroxisome proliferator-activated receptor-? (PPAR?) agonists and suppressed by PPAR? antagonism or NF-?B activation. Reducing A? and neuroinflammation by MAGL inhibition was occluded by PPAR? antagonism. In addition, BACE1 suppression by 2-AG and PPAR? activation was eliminated by knockdown of NF-?B. Our study provides a novel molecular mechanism underlying improved synaptic and cognitive function in TG mice by 2-AG signaling, which upregulates miR-188-3p expression through PPAR? and NF-?B signaling pathway, resulting in suppressions of BACE1 expression and A? formation.

SUBMITTER: Zhang J

PROVIDER: S-EPMC4220026 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer's disease.

Zhang Jian J Hu Mei M Teng Zhaoqian Z Tang Ya-Ping YP Chen Chu C

The Journal of neuroscience : the official journal of the Society for Neuroscience 20141101 45

Abnormal accumulation of β-amyloid (Aβ) is the major neuropathological hallmark of Alzheimer's disease (AD). However, the mechanisms underlying aberrant Aβ formation in AD remain unclear. We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for Aβ formation. How ...[more]

PMID: 25378159

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Project description:The purpose of our study was to identify microRNAs (miRNAs) as early detectable peripheral biomarkers in Alzheimer's disease (AD). To achieve our objective, we assessed miRNAs in serum samples from AD patients and Mild cognitive impairment (MCI) subjects relative to healthy controls. We used Affymetrix microarray analysis and validated differentially expressed miRNAs using qRT-PCR. We further validated miRNA data using AD postmortem brains, amyloid precursor protein transgenic mice and AD cell lines. We identified a gradual upregulation of four miRNAs: miR-455-3p, miR-4668-5p, miR-3613-3p and miR-4674. A fifth miRNA, mir-6722, was down-regulated in persons with AD and mild cognitive impairment compared with controls. Validation analysis by qRT-PCR showed significant upregulation of only miR-455-3p (P?=?0.007) and miR-4668-5p (P?=?0.016) in AD patients compared with healthy controls. Furthermore, qRT-PCR analysis of the AD postmortem brains with different Braak stages also showed upregulation of miR-455-3p (P?=?0.016). However, receiver operating characteristic curves (ROC) curve analysis revealed a significant area under curve (AUC) value only for miR-455-3p in the serum (AUROC?=?0.79; P?=?0.015) and brains (AUROC?=?0.86; P?=?0.016) of AD patients. Expression analysis of amyloid precursor protein transgenic mice also revealed high level of mmu-miR-455-3p (P?=?0.004) in the cerebral cortex (AD-affected) region of brain and low in the non-affected area, i.e. cerebellum. Furthermore, human and mouse neuroblastoma cells treated with the amyloid-?(1-42) peptide also showed a similarly higher expression of miR-455-3p. Functional analysis of differentially expressed miRNAs via the miR-path indicated that miR-455-3p was associated in the regulation of several biological pathways. Genes associated with these pathways were found to have a crucial role in AD pathogenesis. An increase in miR-455-3p expression found in AD patients and A? pathologies unveiled its biomarker characteristics and a precise role in AD pathogenesis.

Dataset Information

Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer's disease.

Publications

Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer's disease.

Similar Datasets

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