MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here we describe a neuroprotective function of miR-132, the miRNA most significantly down-regulated in Alzheimer's disease. miR-132 protects mouse and human wild-type neurons and more vulnerable Tau-mutant primary neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF Tau pathology and neurodegeneration and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7.These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.All rights reserved. No reuse allowed without permission.
Introduction The use of TLR9 agonists as immunomodulators is supported by preclinical and clinical studies, showing their anti-tumor effect by enhancing both cellular and humoral immune responses. So far, two different families of DNA molecules containing non-methylated CG-motifs for TLR9 activation have been established: Dumbbell-shaped dSLIM (R) molecules are protected against exonucleolytic degradation by their covalently-closed, natural phosphodiester (PO) backbone. In contrast, single-stranded, oligodeoxynucleotides (CpG-ODN) are most commonly chemicallystabilized by phosphorothioates (PTO) in their phosphate moieties. PTO modification, however, produce off-target effects in immune cell populations and have resulted in an unfavorable risk-to-benefit ratio.Methods To avoid the off-target effects of PTO-modified CpG-ODN, linear single-stranded ODN were synthezised using L-deoxyribonucleotides at their 3'-ends, which are the natural enantiomers of Ddeoxyribonucleotides. The vast majority of deoxyribose in present organisms are D-deoxyribose, thus co-evolved nucleases are blind for L-deoxyribose thereby leaving L-protected ODN intact. We selected nucleotide sequences of such L-protected, CG-motif containing, single-stranded ODN, EnanDIM (R) , for high secretion of IFN-alpha and IP-10 from human peripheral blood mononuclear cells (PBMC). In a maximum feasible dose approach in CD-1 mice EnanDIM (R) doses of 10 to 50 mg per mice were injected subcutaneously to evaluate the acute toxicity and immunomodulatory properties of EnanDIM (R) molecules in vivo.Results EnanDIM581 and EnanDIM532 were chosen since they caused high secretion of IFN-alpha and IP-10 from human PBMC and resulted in a strong activation of monocytes, NK cells and plasmacytoid dendritic cells (pDC) in vitro. Notably, both showed a distinct immune activation pattern, with the highest secretion of IFNalpha by EnanDIM581 and the strongest maturation of TLR9-bearing pDC by EnanDIM532. EnanDIM744, comprising EnanDIM581 with additional 5'-end L-nucleotide protection and exhibiting an immune activation pattern similar to EnanDIM581, was selected as third EnanDIM (R) for in vivo studies. In the maximum feasible dose approach, safety assessments were performed throughout the study period and no mortality, clinical signs and body weight changes were observed, despite the fact that extremely high doses of app. 300 to 1700 mg/kg were used. A gross necropsy consisting of a macroscopic organ evaluation at day 15 revealed also no toxicity. Regarding immune activation, increased levels of IP-10 in serum were observed 24 hours after injection but not after 15 days confirming that L-nucleotides in EnanDIM (R) do not change the kinetic profile known from other DNA-based TLR9 agonists.Conclusions EnanDIM (R) , a new family of TLR9 agonists with conformation-mediated nuclease-resistance, broadly activates the immune system in vitro. Maximal feasible doses of EnanDIM (R) resulted in no signs of toxicity and confirmed immunomodulatory effects in vivo. Therefore En...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.