Matrix metalloproteinase‐9 expression in the nuclear compartment of neurons and glial cells in aging and stroke

Abstract

Matrix metalloproteinases (MMPs) are well-recognized denominators for extracellular matrix remodeling in the pathology of both ischemic and hemorrhagic strokes. Recent data on non-nervous system tissue showed intracellular and even intranuclear localizations for different MMPs, and together with this, a plethora of new functions have been proposed for these intracellular active enzymes, but are mostly related to apoptosis induction and malign transformation. In neurons and glial cells, on human tissue, animal models and cell cultures, different active MMPs have been also proven to be located in the intra-cytoplasmic or intra-nuclear compartments, with no clear-cut function. In the present study we show for the first time on human tissue the nuclear expression of MMP-9, mainly in neurons and to a lesser extent in astrocytes. We have studied ischemic and hemorrhagic stroke patients, as well as aged control patients. Age and ischemic suffering seemed to be the best predictors for an elevated MMP-9 nuclear expression, and there was no evidence of a clear-cut extracellular proteolytic activity for this compartment, as revealed by intact vascular basement membranes and assessment of vascular densities. More, the majority of the cells expressing MMP-9 in the nuclear compartment also co-expressed activated-caspase 3, indicating a possible link between nuclear MMP-9 localization and apoptosis in neuronal and glial cells following an ischemic or hemorrhagic event. These results, besides showing for the first time the nuclear localization of MMP-9 on a large series of human stroke and aged brain tissues, raise new questions regarding the unknown spectrum of the functions MMPs in human CNS pathology.

Multimodal Imaging Reveals Temporal and Spatial Microglia and Matrix Metalloproteinase Activity after Experimental Stroke

“… 10 Moreover, in our study at 7 days after tMCAo MMP-9 expression was found in cells with fragmented nuclei ( Figure 4 ) suggesting an associated role in apoptotic processes or to cells undergoing secondary necrosis. 40 , 41 Longitudinal in vivo imaging of MMPs, therefore, may allow the investigation of different pathophysiologic processes after tMCAo with early [ 18 F]BR-351 signals resembling activation of MMPs in the vasculature and subsequent blood–brain barrier opening, intermediate time points (7 to 14 days after tMCAo) indicating activation of microglia and apoptosis, and later time points (14 to 21 days after tMCAo) marking MMP-related neoangiogenesis. 10 It has been shown that early inhibition of MMP-9 has a beneficial role, 39 whereas late inhibition has detrimental effects 10 on stroke outcome.…”

Matrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines

“…Within the resting brain, it is mostly synthesized by neurons but to some extent also by glia in such structures as the hippocampus, cerebral cortex, and cerebellum. It is extracellularly secreted, although recent studies have also revealed its presence in the nucleus of muscle cells (Yeghiazaryan et al, 2012), neurons (Yang et al, 2010; Hill et al, 2012), human glial cells (Pirici et al, 2012), and mitochondria of retinal capillary cells. MMP-9 may act as a negative regulator of mitochondrial function and may be involved in apoptosis (Kowluru et al, 2011).…”

Nuclear MMP‐9 role in the regulation of rat skeletal myoblasts proliferation

“…Moreover, MMP-13 was found in the nuclei of neurons after cerebral ischaemia in rat brains (Cuadrado et al, 2009), and ADAMTS13 was present within the nuclei of liver-derived cell lines (Hunt et al, 2011). Nuclear localisation of MMP-9 was detected in human and rat neurons, as well as human glial cells (Yang et al, 2010;Pirici et al, 2011), neuroblastoma cells and bone marrow macrophages (Sans-Fons et al, 2010). Although these MMPs were found within the nuclei their function remain elusive, and so far has only been characterised for MMP-2, which degrades poly(ADP-ribose) polymerase (Kwan et al, 2004).…”