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Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer's disease.
Sci Rep 2017; 7(1):683SR

Abstract

A hallmark of Alzheimer's disease (AD) is the accumulation of oligomeric amyloid-β (Aβ) peptide, which may be primarily responsible for neuronal dysfunction. Insulin signaling provides a defense mechanism against oligomer-induced neuronal loss. We previously described the neuroprotective role of matrix metalloproteinase 9 (MMP-9) in decreasing the formation of Aβ oligomers. In the present study, we examined the role of MMP-9 on the insulin survival pathway in primary hippocampal cultures and hippocampal cell extracts from 3 month-old wild type, AD (5XFAD), MMP-9-overexpressing (TgMMP-9), and double transgenic mice (5XFAD/TgMMP-9). The data demonstrate that the insulin pathway was compromised in samples from 5XFAD mice, when compared to the wild type and TgMMP-9. This was due to enhanced phosphorylation of IRS1 at Serine 636 (pIRS1-Ser636), which renders IRS1 inactive and prevents insulin-mediated signaling. In 5XFAD/TgMMP-9 samples, the insulin survival pathway was rescued through enhanced activation by phosphorylation of IRS1 at Tyrosine 465 (pIRS1-Tyr465), downstream increased phosphorylation of Akt and GSK-3β, and decreased phosphorylation of JNK kinase. Oligomeric Aβ levels decreased and BDNF levels increased in 5XFAD/TgMMP-9 mice, compared to 5XFAD mice. Our findings indicate that overexpression of MMP-9 rescued insulin survival signaling in vitro and in early stages in the 5XFAD model of AD.

Authors+Show Affiliations

Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece. Division of Human and Animal Physiology, Department of Biology, National and Kapodistrian University of Athens, Athens, Greece.Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece.Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece. atzin@bio.demokritos.gr.Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece. effie@bio.demokritos.gr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28386117

Citation

Kaminari, Archontia, et al. "Overexpression of Matrix Metalloproteinase-9 (MMP-9) Rescues Insulin-mediated Impairment in the 5XFAD Model of Alzheimer's Disease." Scientific Reports, vol. 7, no. 1, 2017, p. 683.
Kaminari A, Giannakas N, Tzinia A, et al. Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer's disease. Sci Rep. 2017;7(1):683.
Kaminari, A., Giannakas, N., Tzinia, A., & Tsilibary, E. C. (2017). Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer's disease. Scientific Reports, 7(1), p. 683. doi:10.1038/s41598-017-00794-5.
Kaminari A, et al. Overexpression of Matrix Metalloproteinase-9 (MMP-9) Rescues Insulin-mediated Impairment in the 5XFAD Model of Alzheimer's Disease. Sci Rep. 2017 04 6;7(1):683. PubMed PMID: 28386117.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer's disease. AU - Kaminari,Archontia, AU - Giannakas,Nikolas, AU - Tzinia,Athina, AU - Tsilibary,Effie C, Y1 - 2017/04/06/ PY - 2016/11/29/received PY - 2017/03/13/accepted PY - 2017/4/8/entrez PY - 2017/4/8/pubmed PY - 2018/8/31/medline SP - 683 EP - 683 JF - Scientific reports JO - Sci Rep VL - 7 IS - 1 N2 - A hallmark of Alzheimer's disease (AD) is the accumulation of oligomeric amyloid-β (Aβ) peptide, which may be primarily responsible for neuronal dysfunction. Insulin signaling provides a defense mechanism against oligomer-induced neuronal loss. We previously described the neuroprotective role of matrix metalloproteinase 9 (MMP-9) in decreasing the formation of Aβ oligomers. In the present study, we examined the role of MMP-9 on the insulin survival pathway in primary hippocampal cultures and hippocampal cell extracts from 3 month-old wild type, AD (5XFAD), MMP-9-overexpressing (TgMMP-9), and double transgenic mice (5XFAD/TgMMP-9). The data demonstrate that the insulin pathway was compromised in samples from 5XFAD mice, when compared to the wild type and TgMMP-9. This was due to enhanced phosphorylation of IRS1 at Serine 636 (pIRS1-Ser636), which renders IRS1 inactive and prevents insulin-mediated signaling. In 5XFAD/TgMMP-9 samples, the insulin survival pathway was rescued through enhanced activation by phosphorylation of IRS1 at Tyrosine 465 (pIRS1-Tyr465), downstream increased phosphorylation of Akt and GSK-3β, and decreased phosphorylation of JNK kinase. Oligomeric Aβ levels decreased and BDNF levels increased in 5XFAD/TgMMP-9 mice, compared to 5XFAD mice. Our findings indicate that overexpression of MMP-9 rescued insulin survival signaling in vitro and in early stages in the 5XFAD model of AD. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/28386117/Overexpression_of_matrix_metalloproteinase_9__MMP_9__rescues_insulin_mediated_impairment_in_the_5XFAD_model_of_Alzheimer's_disease_ L2 - http://dx.doi.org/10.1038/s41598-017-00794-5 DB - PRIME DP - Unbound Medicine ER -