title: Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice.
abstract: Accumulation of amyloid-β (Αβ) peptide is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Lowering Aβ levels in the brain may thus improve synaptic and cognitive deficits observed in AD patients. In the non-amyloidogenic pathway, the amyloid-β precursor protein (APP) is cleaved within the Aβ peptide sequence by α-secretases, giving rise to the potent neurotrophic N-terminal fragment sΑPPα. We have previously reported that gelatinase B/matrix metalloproteinase 9 (MMP-9), a matrix metalloproteinase critically involved in neuronal plasticity, acts as α-secretase both in vitro and in vivo and reduces Aβ levels in vitro. In the present study, we demonstrate that neuronal overexpression of MMP-9 in a transgenic AD mouse model harboring five familial AD-related mutations (5xFAD) resulted in increased sAPPα levels and decreased Aβ oligomers without affecting amyloid plaque load in the brain. Functionally, overexpression of MMP-9 prevented the cognitive deficits displayed by 5xFAD mice, an improvement that was accompanied by increased levels of the pre-synaptic protein synaptophysin and mature brain-derived neurotrophic factor (BDNF) in the brain. These results suggest that in vivo activation of endogenous MMP-9 could be a promising target for interference with development and/or progression of AD.
authors.affiliation: Laboratory of Cell & Matrix Pathobiology, Institute of Biology, NCSR Demokritos, Athens, Greece.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Fragkouli
authors.affiliation: Laboratory of Cell & Matrix Pathobiology, Institute of Biology, NCSR Demokritos, Athens, Greece.
authors.forename: Effie C
authors.initials: EC
authors.lastname: Tsilibary
authors.affiliation: Laboratory of Cell & Matrix Pathobiology, Institute of Biology, NCSR Demokritos, Athens, Greece. Electronic address: atzin@bio.demokritos.gr.
authors.forename: Athina K
authors.initials: AK
authors.lastname: Tzinia
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D058225:Plaque, Amyloid / Q000473:pathology / Q000503:physiopathology; D021641:Recognition, Psychology / Q000502:physiology; D012727:Sex Characteristics; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D016708:Synaptophysin; C569015:Syp protein, mouse; D053829:Amyloid Precursor Protein Secretases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: 5xFAD mouse model; Alzheimer's disease; Amyloid beta; MMP-9; α-Secretase