A new role for matrix metalloproteinase-3 in the NGF metabolic pathway: Proteolysis of mature NGF and sex-specific differences in the continuum of Alzheimer's pathology
Por:
Pentz, R, Iulita, MF, Mikutra-Cencora, M, Ducatenzeiler, A, Bennett, DA, Cuello, AC
Publicada:
1 ene 2021
Resumen:
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.
Filiaciones:
Pentz, R:
McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada
Iulita, MF:
McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
Univ Autonoma Barcelona, Biomed Res Inst St Pau, St Pau Memory Unit, Dept Neurol,Hosp Santa Creu & St Pau,Biomed Res I, Barcelona, Spain
Mikutra-Cencora, M:
McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
Ducatenzeiler, A:
McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
Bennett, DA:
Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA
Cuello, AC:
McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada
McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
Univ Oxford, Dept Pharmacol, Oxford, OH USA
gold, Green Accepted
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