| First Author | Zhang J | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 45 | Pages | 14919-33 |
| PubMed ID | 25378159 | Mgi Jnum | J:238184 |
| Mgi Id | MGI:5818431 | Doi | 10.1523/JNEUROSCI.1165-14.2014 |
| Citation | Zhang J, et al. (2014) 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. J Neurosci 34(45):14919-33 |
| abstractText | Abnormal accumulation of beta-amyloid (Abeta) is the major neuropathological hallmark of Alzheimer's disease (AD). However, the mechanisms underlying aberrant Abeta 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 Abeta by inhibiting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for Abeta 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, Abeta, 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-gamma (PPARgamma) agonists and suppressed by PPARgamma antagonism or NF-kappaB activation. Reducing Abeta and neuroinflammation by MAGL inhibition was occluded by PPARgamma antagonism. In addition, BACE1 suppression by 2-AG and PPARgamma activation was eliminated by knockdown of NF-kappaB. 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 PPARgamma and NF-kappaB signaling pathway, resulting in suppressions of BACE1 expression and Abeta formation. |
