Abstract
Matrix metalloproteinases (MMPs) are pleiotropic endopeptidases involved in a variety of neurodegenerative/neuroinflammatory processes through their interactions with a large number of substrates. Among those, the amyloid precursor protein (APP) and the beta amyloid peptide (Aβ) are largely associated with the development of Alzheimer’s disease (AD). However, the regulation and potential contribution of MMPs to AD remains unclear. In this study, we investigated the evolution of the expression of MMP-2, MMP-9, and membrane-type 1-MMP (MT1-MMP) in the hippocampus at different stages of the pathology (asymptomatic, prodromal-like and symptomatic) in the 5xFAD transgenic mouse AD model. In parallel we also followed the expression of functionally associated factors. Overall, the expression of MMP-2, MMP-9, and MT1-MMP was upregulated concomitantly with the tissue inhibitor of MMPs-1 (TIMP-1) and several markers of inflammatory/glial response. The three MMPs exhibited age- and cell-dependent upregulation of their expression, with MMP-2 and MMP-9 being primarily located to astrocytes, and MT1-MMP to neurons. MMP-9 and MT1-MMP were also prominently present in amyloid plaques. The levels of active MT1-MMP were highly upregulated in membrane-enriched fractions of hippocampus at 6 months of age (symptomatic phase), when the levels of APP, its metabolites APP C-terminal fragments (CTFs), and Aβ trimers were the highest. Overexpression of MT1-MMP in HEK cells carrying the human APP Swedish mutation (HEKswe) strongly increased β-secretase derived C-terminal APP fragment (C99) and Aβ levels, whereas MMP-2 overexpression nearly abolished Aβ production without affecting C99. Our data consolidate the emerging idea of a regulatory interplay between MMPs and the APP/Aβ system, and demonstrate for the first time the pro-amyloidogenic features of MT1-MMP. Further investigation will be justified to evaluate this MMP as a novel potential therapeutic target in AD.
Highlights
Alzheimer’s disease (AD) is the most common and devastating neurodegenerative disorder
EXPRESSION OF METALLOPROTEINASES, TIMPs AND INFLAMMATORY MARKERS IN THE HIPPOCAMPUS OF 5xFAD MICE ACROSS AGE To obtain a broad picture of the regulation of metalloproteinases potentially involved in Aβ/amyloid precursor protein (APP) metabolism across different phases of the amyloid pathology, we assessed the mRNA levels of matrix metalloproteinases (MMPs), adamalysins 10 and 17 (ADAM-10 and -17) and classical Aβ-degrading enzymes (NEP, insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE))
Among MMPs, the expression of Mmp-2 and Mmp-9 remained unaffected in 2-month-old mice and was significantly increased 50% and 130% in 5xFAD mice compared to WT at 4 and 6 months, respectively (Figure 1A)
Summary
Alzheimer’s disease (AD) is the most common and devastating neurodegenerative disorder. Matrix metalloproteinases constitute a family of ∼25 zincdependent endopeptidases produced by all neural cell types They interact with a wide range of substrates (e.g., extracellular matrix proteins, cytokines, growth factors, cell adhesion molecules, receptors), which confer to MMPs broad functional diversity (Rivera et al, 2010). They are involved in numerous pathological and physiological processes: neural cell motility and outgrowth (Ogier et al, 2006; Gonthier et al, 2007; Ould-yahoui et al, 2009), neuronal death (Jourquin et al, 2003), synaptic plasticity and cognition (Jourquin et al, 2005; Chaillan et al, 2006; Meighan et al, 2006; Nagy et al, 2006; Kaliszewska et al, 2012), neuroinflammation (Ogier et al, 2005; Hu et al, 2007; Candelario-Jalil et al, 2009) and blood brain barrier (BBB) breakdown (Yang et al, 2007)
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