MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer’s disease (original) (raw)
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MT5-MMP, just a new APP processing proteinase in Alzheimer’s disease?
Journal of Neuroinflammation, 2016
We have recently identified in a transgenic mouse model of Alzheimer's disease (AD) membrane-type 5-MMP (MT5-MMP) as a new player in Alzheimer's pathogenesis, which displays pro-amyloidogenic features and proteolytic processing of amyloid precursor protein (APP). Another group has reported that MT5-MMP processing of APP may release a novel neurotoxic APP fragment. Although MT5-MMP-mediated APP processing appears to be a key pathogenic step, we hypothesize that MT5-MMP may also contribute to AD pathogenesis through complementary mechanisms that involve the activation of pro-inflammatory pathways and/or APP trafficking.
2020
ABSTRACTWe previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by th...
Journal of Neuroscience, 2006
It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between the generation and clearance of the amyloid- peptide (A). Although familial AD appears to be caused by A overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of A. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of A degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular A degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded A, lowering levels and producing several fragments after incubation with synthetic human A 1-40 and A 1-42 . This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp-2 or -9 knock-out (KO) mice. In vivo, significant increases in the steady-state levels of A were found in the brains of mmp-2 and -9 KO mice compared with wild-type controls.
Sequential Abeta degradation by the matrix metalloproteases MMP-2 and MMP-9
The Journal of biological chemistry, 2015
Matrix metalloproteases MMP-2 and MMP-9 have been implicated in the physiologic catabolism of Alzheimer amyloid-β (Aβ). Conversely, their association with vascular amyloid deposits, blood-brain barrier disruption, and hemorrhagic transformations after ischemic stroke also highlights their involvement in pathologic processes. To better understand this dichotomy, recombinant human (rh) MMP-2 and MMP-9 were incubated with Aβ40 and Aβ42 and the resulting proteolytic fragments assessed via immunoprecipitation and quantitative mass spectrometry. Both MMPs generated Aβ fragments truncated only at the C-terminus, ending at positions 34, 30 and 16. Using deuterated homologues as internal standards, we observed limited and relatively slow degradation of Aβ42 by rhMMP-2 while the enzyme cleaved >80% of Aβ40 during the first hour of incubation. rhMMP-9 was significantly less effective, particularly in degrading Aβ1-42, although the targeted peptide bonds were identical. Using Aβ1-34 and Aβ1-...
Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice
Neurobiology of Disease, 2014
Accumulation of amyloid-β (Αβ) peptide is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Lowering Aβ levels in the brain may thus improve synaptic and cognitive deficits observed in AD patients. In the non-amyloidogenic pathway, the amyloid-β precursor protein (APP) is cleaved within the Aβ peptide sequence by α-secretases, giving rise to the potent neurotrophic N-terminal fragment sΑPPα. We have previously reported that gelatinase B/matrix metalloproteinase 9 (MMP-9), a matrix metalloproteinase critically involved in neuronal plasticity, acts as α-secretase both in vitro and in vivo and reduces Aβ levels in vitro. In the present study, we demonstrate that neuronal overexpression of MMP-9 in a transgenic AD mouse model harboring five familial AD-related mutations (5xFAD) resulted in increased sAPPα levels and decreased Aβ oligomers without affecting amyloid plaque load in the brain. Functionally, overexpression of MMP-9 prevented the cognitive deficits displayed by 5xFAD mice, an improvement that was accompanied by increased levels of the pre-synaptic protein synaptophysin and mature brain-derived neurotrophic factor (BDNF) in the brain. These results suggest that in vivo activation of endogenous MMP-9 could be a promising target for interference with development and/or progression of AD.
Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism
The Journal of Neuroscience, 2006
It has been postulated that the development of amyloid plaques in Alzheimer's disease (AD) may result from an imbalance between the generation and clearance of the amyloid-β peptide (Aβ). Although familial AD appears to be caused by Aβ overproduction, sporadic AD (the most prevalent form) may result from impairment in clearance. Recent evidence suggests that several proteases may contribute to the degradation of Aβ. Furthermore, astrocytes have recently been implicated as a potential cellular mediator of Aβ degradation. In this study, we examined the possibility that matrix metalloproteinases (MMPs), proteases known to be expressed and secreted by astrocytes, could play a role in extracellular Aβ degradation. We found that astrocytes surrounding amyloid plaques showed enhanced expression of MMP-2 and MMP-9 in aged amyloid precursor protein (APP)/presenilin 1 mice. Moreover, astrocyte-conditioned medium (ACM) degraded Aβ, lowering levels and producing several fragments after incu...
Matrix metalloproteinases and their multiple roles in Alzheimer's disease
BioMed research international, 2014
Alzheimer's disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), as well as neuronal death and synaptic loss. Matrix metalloproteinases (MMPs) play an important role as inflammatory components in the pathogenesis of AD. MMP-2 might be assumed to have a protective role in AD and is the major MMP which is directly linked to Aβ in the brain. Synthesis of MMP-9 can be induced by Aβ, and the enzymes appear to exert multiple effects in AD in senile plaque homoeostasis. The proaggregatory influence on tau oligomer formation in strategic brain regions may be a potential neurotoxic side effect of MMP-9. MMP-3 levels are correlated to the duration of AD and correlate with the CSF T-tau and P-tau levels in the elderly controls. Elevated brain levels of MMP-3 might result in increased MMP-9 activity and indirectly facilitate tau aggregation. At present, the clinical utility of these prote...
Frontiers in molecular neuroscience, 2016
We previously reported that deficiency of membrane-type five matrix metalloproteinase (MT5-MMP) prevents amyloid pathology in the cortex and hippocampus of 5xFAD mice, and ameliorates the functional outcome. We have now investigated whether the integrity of another important area affected in Alzheimer's disease (AD), the frontal cortex, was also preserved upon MT5-MMP deficiency in 4-month old mice at prodromal stages of the pathology. We used the olfactory H-maze (OHM) to show that learning impairment associated with dysfunctions of the frontal cortex in 5xFAD was prevented in bigenic 5xFAD/MT5-MMP(-/-) mice. The latter exhibited concomitant drastic reductions of amyloid beta peptide (Aβ) assemblies (soluble, oligomeric and fibrillary) and its immediate precursor, C99. Simultaneously, astrocyte reactivity and tumor necrosis factor alpha (TNF-α) levels were also lowered. Moreover, MT5-MMP deficiency induced a decrease in N-terminal soluble fragments of amyloid precursor protein ...
Journal of Clinical Investigation, 2004
Alzheimer disease (AD) is characterized by excessive deposition of amyloid β-peptides (Aβ peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the α-secretase within the Aβ peptide sequence. Proteinases of the ADAM family (a disintegrin and metalloproteinase) are the main candidates as physiologically relevant α-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP [V717I] increased the secretion of the neurotrophic soluble α-secretase-released N-terminal APP domain (APPsα), reduced the formation of Aβ peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an α-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in α-secretase activity contributes to the development of AD.
Frontiers in aging neuroscience, 2014
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-de...