title: Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer's disease.
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.affiliation: 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.
authors.forename: Archontia
authors.initials: A
authors.lastname: Kaminari
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Giannakas
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece. atzin@bio.demokritos.gr.
authors.forename: Athina
authors.initials: A
authors.lastname: Tzinia
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Agia Paraskevi, Athens, 15310, Greece. effie@bio.demokritos.gr.
authors.forename: Effie C
authors.initials: EC
authors.lastname: Tsilibary
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020813:Receptor, trkB
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; C526295:Irs1 protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB