Enhanced neuronal plasticity and elevated endogenous sAPPα levels in mice over-expressing MMP9

• Published in: Journal of neurochemistry 2012-04, Vol.121 (2), p.239-251
• Main Authors: Fragkouli, Apostolia, Papatheodoropoulos, Costas, Georgopoulos, Spiros, Stamatakis, Antonios, Stylianopoulou, Fotini, Tsilibary, Effie C., Tzinia, Athina K.
• Format: Article
• Language: English
• Subjects: Ageing, cell death; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Biological and medical sciences; Blotting, Western; Brain - enzymology; Brain - physiology; Brain slice preparation; Cell physiology; Cerebral Cortex - cytology; Cerebral Cortex - physiology; Cognition - physiology; Cognitive ability; Cortex; Dendritic spines; Dendritic Spines - physiology; DNA - genetics; Electrophysiological Phenomena; Experimental viral diseases and models; Exploratory Behavior - physiology; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gelatinase B; Hippocampus; Hippocampus - cytology; Hippocampus - physiology; Humans; Infectious diseases; learning and memory; Long-Term Potentiation - genetics; Long-Term Potentiation - physiology; LTP; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - physiology; Maze Learning - physiology; Medical sciences; Memory; Mice; Mice, Transgenic; MMP9; Molecular and cellular biology; neuronal plasticity; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Neurons; Overexpression; Pattern recognition; Peptide Fragments - metabolism; Plasticity (neural); Plasticity (synaptic); Potentiation; Proteolysis; Psychomotor Performance - physiology; Real-Time Polymerase Chain Reaction; Receptor, Platelet-Derived Growth Factor beta - genetics; Recognition, Psychology - physiology; Secretion; soluble APPα; Transgenic mice; Viral diseases; α-secretase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07637.x

J. Neurochem. (2012) 121, 239–251. Evidence accumulating during the past few years points to a significant role of matrix metalloproteinase 9 (MMP9) enzymatic activity in synaptic plasticity and cognitive processes. We have previously demonstrated that MMP9 is involved in receptor‐mediated α‐secretase‐like cleavage of APP in vitro, resulting in increased secretion of sAPPα, the soluble N‐terminal product of the non‐amyloidogenic pathway known to be involved in neuronal plasticity and memory formation. To study the in vivo role of MMP9, we have generated transgenic mice over‐expressing MMP9 in the brain. Herein, we demonstrate that MMP9 transgenic animals display enhanced performance in the non‐spatial novel object recognition and the spatial water‐maze task and that their enhanced performance was accompanied by increased dendritic spine density in the hippocampus and cortex following behavioural testing. Consistent with the above observations, the electrophysiological analysis revealed prolonged maintenance of long‐term synaptic potentiation in hippocampal slices from MMP9 transgenic mice. Moreover, elevated sAPPα levels in the hippocampus and cortex of MPP9 transgenic animals were also observed. Overall, our results extend previous findings on the physiological role of MMP9 in neuronal plasticity and furthermore reveal that, APP may be one of the physiological proteolytic targets of MMP9 in vivo. Beneficial effects of MMP9 in the brain 
To investigate MMP9 effect on neuronal plasticity in vivo, we have generated a transgenic mouse line over‐expressing MMP9 in brain neurons. Over‐expression of MMP9 in the brain results to enhanced synaptic plasticity, improved cognitive abilities and increased secretion of the neurotrophic sAPPα. APP may be a physiological target of MMP9 and sAPPα might participate in MMP9 plasticity‐enhancing effects in vivo.