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

Jian Zhang, Mei Hu, Zhaoqian Teng, Ya Ping Tang, Chu Chen

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

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. 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, Aβ, 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-γ (PPARγ) agonists and suppressed by PPARγ antagonism or NF-κB activation. Reducing Aβ and neuroinflammation by MAGL inhibition was occluded by PPARγ antagonism. In addition, BACE1 suppression by 2-AG and PPARγ activation was eliminated by knockdown of NF-κB. 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 PPARγ and NF-κB signaling pathway, resulting in suppressions of BACE1 expression and Aβ formation.

Original languageEnglish (US)
Pages (from-to)14919-14933
Number of pages15
JournalJournal of Neuroscience
Volume34
Issue number45
DOIs
StatePublished - Nov 5 2014
Externally publishedYes

Keywords

  • Endocannabinoids
  • Monoacylglycerol lipase
  • NF-κB
  • Noncoding small RNA
  • PPARγ
  • miRNA sponge

ASJC Scopus subject areas

  • General Neuroscience

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