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Enhanced neuronal plasticity and elevated endogenous sAPPα levels in mice over-expressing MMP9
Apostolia Fragkouli1, Costas Papatheodoropoulos, Spiros Georgopoulos
1Laboratory of Cell & Matrix Pathobiology, Institute of Biology, NCSR Demokritos, Athens, Greece. apostoliafragkouli@gmail.com
Abstract:
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.
Insights
Matrix metalloproteinase 9 (MMP9) enhances cognitive function and synaptic plasticity. Overexpressing MMP9 in mice improved memory and learning, suggesting APP is a key target.
Area of Science:
- Neuroscience
- Molecular Biology
- Enzymology
Background:
- Matrix metalloproteinase 9 (MMP9) enzymatic activity is increasingly linked to synaptic plasticity and cognitive functions.
- Previous in vitro studies implicated MMP9 in the alpha-secretase-like cleavage of amyloid precursor protein (APP), boosting neuroprotective sAPPα secretion.
- The in vivo role of MMP9 in cognitive processes remains to be fully elucidated.
Purpose of the Study:
- To investigate the in vivo physiological role of MMP9 in synaptic plasticity and cognitive performance.
- To determine if MMP9 overexpression in the brain impacts cognitive behaviors and neuronal structure.
- To explore the relationship between MMP9, APP processing, and neuronal function in a transgenic mouse model.
Main Methods:
- Generation of transgenic mice overexpressing MMP9 in the brain.
- Behavioral testing using novel object recognition and spatial water-maze tasks.
- Assessment of dendritic spine density in hippocampal and cortical tissues.
- Electrophysiological analysis of long-term potentiation (LTP) in hippocampal slices.
- Quantification of soluble APPα (sAPPα) levels in brain tissue.
Main Results:
- MMP9 transgenic mice exhibited enhanced performance in both non-spatial and spatial memory tasks.
- Increased dendritic spine density was observed in the hippocampus and cortex of MMP9 transgenic mice post-behavioral testing.
- Prolonged maintenance of long-term synaptic potentiation was recorded in hippocampal slices from these mice.
- Elevated levels of sAPPα were detected in the hippocampus and cortex of MMP9 transgenic animals.
Conclusions:
- Overexpression of MMP9 in the brain enhances cognitive performance and synaptic plasticity in vivo.
- These findings support a significant physiological role for MMP9 in neuronal plasticity and memory formation.
- Amyloid precursor protein (APP) processing by MMP9, leading to increased sAPPα, is a likely mechanism underlying these observed effects.
