PMID- 25407931 OWN - NLM STAT- MEDLINE DCOM- 20161102 LR - 20220408 IS - 1559-1182 (Electronic) IS - 0893-7648 (Print) IS - 0893-7648 (Linking) VI - 53 IP - 1 DP - 2016 Jan TI - MiR-126 Regulates Growth Factor Activities and Vulnerability to Toxic Insult in Neurons. PG - 95-108 LID - 10.1007/s12035-014-8989-x [doi] AB - Dysfunction of growth factor (GF) activities contributes to the decline and death of neurons during aging and in neurodegenerative diseases. In addition, neurons become more resistant to GF signaling with age. Micro (mi)RNAs are posttranscriptional regulators of gene expression that may be crucial to age- and disease-related changes in GF functions. MiR-126 is involved in regulating insulin/IGF-1/phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling, and we recently demonstrated a functional role of miR-126 in dopamine neuronal cell survival in models of Parkinson's disease (PD)-associated toxicity. Here, we show that elevated levels of miR-126 increase neuronal vulnerability to ubiquitous toxicity mediated by staurosporine (STS) or Alzheimer's disease (AD)-associated amyloid beta 1-42 peptides (Abeta1-42). The neuroprotective factors IGF-1, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and soluble amyloid precursor protein alpha (sAPPalpha) could diminish but not abrogate the toxic effects of miR-126. In miR-126 overexpressing neurons derived from Tg6799 familial AD model mice, we observed an increase in Abeta1-42 toxicity, but surprisingly, both Abeta1-42 and miR-126 promoted neurite sprouting. Pathway analysis revealed that miR-126 overexpression downregulated elements in the GF/PI3K/AKT and ERK signaling cascades, including AKT, GSK-3beta, ERK, their phosphorylation, and the miR-126 targets IRS-1 and PIK3R2. Finally, inhibition of miR-126 was neuroprotective against both STS and Abeta1-42 toxicity. Our data provide evidence for a novel mechanism of regulating GF/PI3K signaling in neurons by miR-126 and suggest that miR-126 may be an important mechanistic link between metabolic dysfunction and neurotoxicity in general, during aging, and in the pathogenesis of specific neurological disorders, including PD and AD. FAU - Kim, Woori AU - Kim W AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - Noh, Haneul AU - Noh H AD - Department of Molecular and Life Sciences, Hanyang University, Ansan, South Korea. FAU - Lee, Yenarae AU - Lee Y AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - Jeon, Jeha AU - Jeon J AD - Department of Molecular and Life Sciences, Hanyang University, Ansan, South Korea. FAU - Shanmugavadivu, Arthi AU - Shanmugavadivu A AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - McPhie, Donna L AU - McPhie DL AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - Kim, Kwang-Soo AU - Kim KS AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - Cohen, Bruce M AU - Cohen BM AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. FAU - Seo, Hyemyung AU - Seo H AD - Department of Molecular and Life Sciences, Hanyang University, Ansan, South Korea. FAU - Sonntag, Kai C AU - Sonntag KC AD - Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, 115 Mill Street, Belmont, MA, 02478, USA. ksonntag@mclean.harvard.edu. LA - eng GR - R01 NS070577/NS/NINDS NIH HHS/United States GR - R21 NS067335/NS/NINDS NIH HHS/United States GR - NS067335/NS/NINDS NIH HHS/United States GR - NS070577/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141119 PL - United States TA - Mol Neurobiol JT - Molecular neurobiology JID - 8900963 RN - 0 (Amyloid beta-Peptides) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (MIRN126 microRNA, rat) RN - 0 (MicroRNAs) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Alzheimer Disease/*metabolism/pathology MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Survival/physiology MH - Cells, Cultured MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Glycogen Synthase Kinase 3/metabolism MH - MicroRNAs/*metabolism MH - Neurons/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Rats, Sprague-Dawley PMC - PMC4437970 MID - NIHMS643501 OTO - NOTNLM OT - Abeta OT - Growth factors OT - MiR-126 OT - Neuroprotection OT - Neurotoxicity OT - PI3K/AKT signaling COIS- Conflict of Interest The authors have no conflicts of interest. EDAT- 2014/11/20 06:00 MHDA- 2016/11/03 06:00 PMCR- 2017/01/01 CRDT- 2014/11/20 06:00 PHST- 2014/07/10 00:00 [received] PHST- 2014/11/04 00:00 [accepted] PHST- 2014/11/20 06:00 [entrez] PHST- 2014/11/20 06:00 [pubmed] PHST- 2016/11/03 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - 10.1007/s12035-014-8989-x [pii] AID - 10.1007/s12035-014-8989-x [doi] PST - ppublish SO - Mol Neurobiol. 2016 Jan;53(1):95-108. doi: 10.1007/s12035-014-8989-x. Epub 2014 Nov 19.