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

Abstract

J. Neurochem. (2012) 121, 239–251. 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.

Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer’s disease

“…The generation of 5XFAD and TgMMP-9, respectively, has been previously reported 28, 48 . Briefly, 5XFAD mice co-express and co-inherit FAD mutant forms of human APP [Swedish (K670N, M671L), Florida (I716V) and London (V717I) mutation] and presenilin-1 (M146L; L286V) transgenes under the transcriptional control of the neuron-specific mouse Thy-1 promoter, whereas TgMMP-9 mice express the wild-type human pro-MMP-9 sequence under the transcriptional control of the neuron-specific promoter platelet-derived growth factor (PDGF)-β.…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…Notably, MMP-9 has been shown to mediate morphological changes in dendritic spines after synaptic stimulation (see above), and it might be potentially involved in dendritic spine pathology in schizophrenia. Furthermore, Fragkouli et al 44 and Gkogkas et al 45 reported an increase in dendritic spine density in the hippocampus and cortex in transgenic mice that overexpress MMP-9.…”

Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders

“…MMP-9, which is expressed in an activity-dependent manner, is important for normal synaptic plasticity, but it also has α-secretase activity. This notion is supported by observations that MMP-9-overexpressing transgenic mice have elevated levels of sAPPα, greater LTP in the hippocampus, and enhanced memory (Fragkouli et al, 2012). Furthermore, MMP-9 overexpression in a mouse model of AD reduced the level of Aβ and its oligomers in the brain and restored learning deficits to the levels of wildtype animals (Fragkouli et al, 2014).…”