Abstract
Matrix metalloproteinase-3 (MMP-3) has been associated with risk of Alzheimer's disease (AD). In this study we introduce a novel role for MMP-3 in degrading nerve growth factor (NGF) in vivo and examine its mRNA and protein expression across the continuum of AD pathology. We provide evidence that MMP-3 participates in the degradation of mature NGF in vitro and in vivo and that it is secreted from the rat cerebral cortex in an activity-dependent manner. We show that cortical MMP-3 is upregulated in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis. A similar upregulation was found in AD and MCI brains as well as in cognitively normal individuals with elevated amyloid deposition. We also observed that frontal cortex MMP-3 protein levels are higher in males. MMP-3 protein correlated with more AD neuropathology, markers of NGF metabolism, and lower cognitive scores in males but not in females. These results suggest that MMP-3 upregulation in AD might contribute to NGF dysmetabolism, and therefore to cholinergic atrophy and cognitive deficits, in a sex-specific manner. MMP-3 should be further investigated as a biomarker candidate or as a therapeutic target in AD.
Highlights
Matrix metalloproteinase-3 (MMP-3) is a multifunctional brain protease with key roles in the developing and adult nervous system
Past work demonstrating that matrix metallo-proteinase-9 (MMP-9) and MMP-3 target sequences overlap (Eckhard et al, 2016), that MMP-3 can be released in response to cholinergic stimulation (De Couto et al, 2009; Reina et al, 2011), and that MMP-3 was elevated in Alzheimer’s disease (AD) cerebrospinal fluid (CSF) where it correlated to cognitive decline (Hanzel et al, 2014) led us to consider the possibility that MMP-3 could be an Mature NGF (mNGF)-degrading protease like MMP-9 in the context of the proposed nerve growth factor (NGF) metabolic pathway (Bruno and Cuello, 2006)
We demonstrate for the first time a role for MMP-3 in the proteolysis of mNGF and, its involvement in the NGF dysmetabolism unleashed by AD pathology (Figure 6), predominantly by amyloid accumulation
Summary
Matrix metalloproteinase-3 (MMP-3) is a multifunctional brain protease with key roles in the developing and adult nervous system. Polymorphisms in the coding region of MMP-3 have been linked to increased risk of Alzheimer’s disease (AD) (Helbecque et al, 2007; Saarela et al, 2004), while MMP-3 in cerebrospinal fluid (CSF) and in plasma has been demonstrated to be altered in AD and to correlate with cognitive impairment and core AD biomarkers (Hanzel et al, 2014; Horstmann et al, 2010; Iulita et al, 2019; Peng et al, 2015; Stomrud et al, 2010a). Mature NGF (mNGF) is produced from its precursor (proNGF) by the plasmin activating system and is subsequently degraded by matrix metallo-proteinase-9 (MMP-9) (Bruno and Cuello, 2006). The enzymes and zymogens involved in the NGF metabolic pathway are secreted at cortical/ hippocampal cholinergic terminal regions in response to glutamatergic or cholinergic stimulation to produce a controlled trophic response (Bruno and Cuello, 2006)
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