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Matrix Metalloproteinase-9 Degrades Amyloid-β Fibrils in Vitro and Compact Plaques in Situ
Open accessAbstract
The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAbeta and that this ability is not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAbeta was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAbeta breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAbeta were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Abeta that are cleaved during its degradation. Only MMP-9 digests contained fragments (Abeta(1-20) and Abeta(1-30)) from fAbeta(1-42) substrate; the corresponding cleavage sites are thought to be important for beta-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fAbeta and may contribute to ongoing clearance of plaques from amyloid-laden brains.
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“and that MMP-9 is capable of degrading amyloid fibrils in vitro and amyloid plaques in situ (61).”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [61]
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“We have previously found that the expression of MMP-9 is up-regulated in reactive astrocytes surrounding plaques (61, 62)”
From Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice (2013) · cites this paper as [61]
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“Enhanced expression of MMP-2 and MMP-9 has been found in astrocytes surrounding amyloid plaques and in the neurons and glia of the hippocampus after intracerebroventricular Ab injection (25)(26)(27)(28).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [26]
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“While MMPs might be involved in processing Ab and clearing plaques, they are likely not major players in this process.(219,229) Thus, MMPs are increased in the AD brain, but the role of MMPs in AD is unknown.”
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Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
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Mueller-Steiner, S., Zhou, Y., Arai, H., Roberson, E. D., Sun, B., Chen, J., Wang, X., Yu, G.-Q., Esposito, L., Mucke, L., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.027 · Cited by 482
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Cauwe, B., den Steen, P. E. V., & Opdenakker, G. (2007) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230701340019 · Cited by 389
“Furthermore, MMP-9 is expressed in astrocytes surrounding plaques in the brains of aged APP/PS1 mice, and its activity is specifically detected in compact plaques (Yan et al., 2006).”
BackgroundMMP ‐9 in translation: from molecule to brain physiology, pathology, and therapy
Vafadari, B., Salamian, A., & Kaczmarek, L. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13415 · Cited by 393
“Moreover, Yan et al. (2006) reported that MMP-9 can degrade aggregated Ab fibrils and that the enzyme is induced by the presence of Ab, especially in reactive astrocytes that surround amyloid plaque.”
BackgroundProteolytic Degradation of Amyloid -Protein
Saido, T., & Leissring, M. A. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006379 · Cited by 368
Astrocyte Biomarkers in Alzheimer’s Disease
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Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease
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“When compared to other degrading proteases, such as ECE, IDE, and NEP, MMP-9 was found to be unique in its ability to degrade A fibrils in vitro and within compact plaques in situ, liberating A fragments 1-20 and 1-30 by cleaving sites within the hairpin loop formation of the sheet structure [186, 188].”
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Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., et al. (2013) · The FASEB Journal · doi:10.1096/fj.12-208660 · Cited by 324
“astrocytes surrounding plaques (61, 62) and that”
Self-citationLee, J. K., Jin, H. K., Endo, S., Schuchman, E. H., Carter, J., & Bae, J.-S. (2009) · Stem Cells · doi:10.1002/stem.277 · Cited by 308
Self-citationThe identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308
Huang, H.-C., & Jiang, Z.-F. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-0960 · Cited by 278
“…neprilysin(NEP) [25,26],endothelincon-verting enzyme (ECE)-1 [27], insulin degrading enzyme (IDE) [28,29], angiotensin converting enzyme (ACE) [30], cathepsin D [31], gelatinase A [32], matrix metalloendopeptidase-9 (MMP-9) [33], coagulation factor XIa [34] and α 2-macroglobulin complexes [35].”
Lee, H. J., Lee, J. K., Lee, H.-W., Carter, J., Chang, J. W., Oh, W., Yang, Y. S., Suh, J., Lee, B., Jin, H. K., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.024 · Cited by 291
“Microglia secrete proteolytic enzymes that degrade A , such as IDE (insulin-degrading enzyme), NEP (neprilysin), MMP-9 (matrix metalloproteinase 9), and plasminogen (Leissring et al., 2003; Yan et al., 2006).”
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Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 292
“MMP-9 has been shown to degrade compact plaques [186, 187] as well as soluble Aβ42 and Aβ40 [167].”
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Miners, J. S., Barua, N., Kehoe, P. G., Gill, S., & Love, S. (2011) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182345e46 · Cited by 265
“The levels of several other candidate AA-degrading proteases, namely, ECE-2 (31), MMP-2 and MMP-9 (64, 173), CTSB (32, 174, 175), and APEH (70), were reported to be elevated in AD; however, in other studies, the concentrations and activities of MMP-2, MMP-3, MMP-9, and plasmin were not increased (120, 124).”
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Targeting the neural extracellular matrix in neurological disorders
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“Importantly, MMP-9 degrades Ab fibrils in vitro or in compact plaques in situ (Yan et al., 2006).”
BackgroundCombined Angiotensin Receptor Antagonism and Neprilysin Inhibition
Hubers, S. A., & Brown, N. (2016) · Circulation · doi:10.1161/circulationaha.115.018622 · Cited by 232
“The mechanisms of action of ARBs such as valsartan have been studied extensively, are reviewed elsewhere, and are not addressed in detail here.(4) In brief, ARBs decrease vasoconstriction and aldosterone production and increase natriuresis by gest on July (2)2, 2018 http://ciajournals.”
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Mechanisms of Amyloid-β Peptide Clearance: Potential Therapeutic Targets for Alzheimer's Disease
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“The levels of ECE-1 (Wang et al., 2009a), ECE-2 (Palmer et al., 2009), MMP-2 (Yan et al., 2006), MMP3, MMP-9 (Bruno et al., 2009) and ACE-2 were reported to increase in AD, but other studies showed no alterations in those of MMP-2, MMP-3, and MMP-9 (Baig et al., 2008).”
ResultMultifaceted role of matrix metalloproteinases (MMPs)
Singh, D. K., Srivastava, S. K., Chaudhuri, T. K., & Upadhyay, G. (2015) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2015.00019 · Cited by 196
“At one hand it directly degrade Aβ resulting in reduction in Aβ deposit (Yan et al., 2006; Miners et al., 2008); then again, these could contribute to brain parenchymal destruction when induced by Aβ in microglia, astrocytes or vascular smooth muscle cells.”
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“In addition, ECE-1, plasmin, and MMP-9 also participate in Aβ degradation [58, 59], and compelling data support a major role of MMP-9 in the degradation of Aβ compact plaques [60, 61], demonstrating its potent role in Aβ clearance.”
Tudorache, I. F., Trusca, V. G., & Gafencu, A. V. (2017) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2017.05.003 · Cited by 186
“pression, can be correlated with AD pathogenesis [81].”
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“also been shown to be induced by A [24–27] and furthermore MMP−2, −3 and −9 are all able to degrade A in vitro [28, 29].”
Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease
Al-Ghraiybah, N. F., Wang, J., Alkhalifa, A. E., Roberts, A. B., Raj, R., Yang, E., & Kaddoumi, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810572 · Cited by 212
Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease?
Nalivaeva, N. N., Beckett, C., Belyaev, N. D., & Turner, A. J. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07510.x · Cited by 169
“…and, of these, MMP-2, -3, -6 and -9 have been reported to degrade Ab1-40, although most attention has focused on MMP-2 (gelatinase A) (Roher et al. 1994) and MMP-9 (gelatinase B) (Backstrom et al. 1996), which can also degrade the fibrillar form of Ab, as well as compact plaques (Yan et al. 2006).”
BackgroundAmyloid β Oligomers Disrupt Blood–CSF Barrier Integrity by Activating Matrix Metalloproteinases
Brkić, M., Balusu, S., Wonterghem, E. V., Gorlé, N., Benilova, I., Kremer, A., Hove, I. V., Moons, L., Strooper, B. D., Kanazir, S., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0006-15.2015 · Cited by 192
“For example, CSF and brain MMP levels are higher in Alzheimer’s disease patients than in age-matched controls and MMPs have been implicated in degradation of A (Guo et al., 2006; Yan et al., 2006; Yin et al., 2006; Hanzel et al., 2014; Kauwe et al., 2014; Mroczko et al., 2014).”
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Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy
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“NEP can degrade soluble A but not aggregated fibrils of the peptide.(42) Most of the GuHCl-extracted brain A measured in the 13-month-old animals probably existed as protease-resistant extracellular deposits (ie, plaques and CAA) in vivo.”
BackgroundSelf-citationTargeting amyloid clearance in Alzheimer's disease as a therapeutic strategy
Nalivaeva, N. N., & Turner, A. J. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14593 · Cited by 177
Microglial degeneration in the aging brain - bad news for neurons?
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“On the other hand, recent studies show that neprilysin cannot degrade the fibrillar beta-amyloid commonly found in dense plaques (182) or especially neurotoxic oligomeric beta-amyloid (183).”
CCL11 enhances excitotoxic neuronal death by producing reactive oxygen species in microglia
Parajuli, B., Horiuchi, H., Mizuno, T., Takeuchi, H., & Suzumura, A. (2015) · Glia · doi:10.1002/glia.22892 · Cited by 163
“Neuronal survival was assessed by MAP-2–specific immunofluorescence staining, as described previously (Mizuno et al., 2008, 2011; Yan et al., 2006).”
MethodAlzheimer Disease and Its Growing Epidemic
Hickman, R. A., Faustin, A., & Wısnıewskı, T. (2016) · Neurologic Clinics · doi:10.1016/j.ncl.2016.06.009 · Cited by 163
“Neprilysin, metalloproteinase-9, and several other factors that are released by healthy microglia digest Ab.98 There is a heightened neuroinflammatory response following TBI that persists, and the activation of microglia most likely releases factors that assist in the digestion of Ab.”
BackgroundIncreased Matrix Metalloproteinase 9 Activity in Mild Cognitive Impairment
Bruno, M. A., Mufson, E. J., Wuu, J., & Cuello, A. C. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181c22569 · Cited by 163
“with ApoE ?4 allele (%) 1 (12) 2 (18) 4 (40) 7 (24) p = 0.”
The Neurovascular Unit in Health and Disease
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“MMP-9, a protease that degrades A , is expressed at higher levels in the brains of AD patients and may play an important role in amyloid clearance by degrading both oA and fA .(10) MMP-9 expression is increased by serum amyloid A through formyl peptide receptor-like-1.”
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Uddin, M. S., & Lim, L. W. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101622 · Cited by 154
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Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity
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“EDTA is a strong inhibitor of metalloproteinases, and matrix metalloproteinase 2 (MMP2) and MMP9 have previously been implicated as major Aβ-degrading enzymes (Yan et al., 2006; Hernandez-Guillamon et al., 2010).”
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Kauwe, J. S. K., Bailey, M. H., Ridge, P. G., Perry, R., Wadsworth, M. E., Hoyt, K. L., Staley, L. A., Karch, C. M., Harari, O., Cruchaga, C., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004758 · Cited by 125
“MMP9 can degrade fibrillar Ab in vitro and plaques in hippocampal slice cultures [52,56,57].”
Self-citationUltrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology
El Hajj, H., Savage, J. C., Bisht, K., Parent, M., Vallières, L., Rivest, S., & Tremblay, M.-È. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1473-9 · Cited by 119
“Additionally, microglia were involved in extracellular degradation of Aβ both in vitro and in vivo [29, 30].”
BackgroundDiversity of astroglial responses across human neurodegenerative disorders and brain aging
Ferrer, I. (2017) · Brain Pathology · doi:10.1111/bpa.12538 · Cited by 135
“The mechanisms used by reactive astrocytes to degrade b-amyloid are multiple and complementary, including activation of metalloproteinases (480, 485) and lysosomal degradation (30, 249, 477).”
BackgroundKurapati, K. R. V., Atluri, V. S. R., Samikkannu, T., & Nair, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077624 · Cited by 130
“angiotensin-converting enzyme, plasminogen activator and matrix metalloproteinase-9 [58-62].”
BackgroundHuman neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease
McGinley, L. M., Kashlan, O. N., Bruno, E. S., Chen, K. S., Hayes, J. M., Kashlan, S. R., Raykin, J., Johe, K. K., Murphy, G. G., & Feldman, E. L. (2018) · Scientific Reports · doi:10.1038/s41598-018-33017-6 · Cited by 136
Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques
Kumar‐Singh, S. (2008) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00380.x · Cited by 101
“Other molecules with similar function and of potential therapeutic relevance are AchE (Rees et al. 2003) and ganglioside GM1 (Yanagisawa et al. 1995).”
BackgroundStargardt, A., Swaab, D. F., & Bossers, K. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.014 · Cited by 109
“In addition to NEP, the matrix metalloproteinase-9 (MMP-9) has received considerable attention for its Ab degrading capacity (Backstrom et al., 1996; Merlo and Sortino, 2012; Yan et al., 2006) and its ability to elevate secreted APPa levels, the product of the nonamyloidogenic pathway of APP processing (Fragkouli et a…”
Sequential Amyloid-β Degradation by the Matrix Metalloproteases MMP-2 and MMP-9
Hernandez-Guillamon, M., Mawhirt, S., Blais, S., Montaner, J., Neubert, T. A., Rostagno, A., & Ghiso, J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.610931 · Cited by 137
“In contrast, MMP-9 has been reported to partially degrade preformed A fibrils (9), generating few identifiable truncated fragments (A (1–20) and A (1–30)) that do not match the sequence of events described in our studies employing soluble A 40 and A 42 homologues.”
BackgroundMatrix Metalloproteinases and Their Multiple Roles in Alzheimer's Disease
Wang, X.-X., Tan, M.-S., Yu, J.-T., & Tan, L. (2014) · BioMed Research International · doi:10.1155/2014/908636 · Cited by 55
“MMP-9 induces Aβ, degrades Aβ and compact plaques, and is released, along with proNGF, in an activity dependent manner [24].”
Cathepsin B Degrades Amyloid-β in Mice Expressing Wild-type Human Amyloid Precursor Protein
Wang, C., Sun, B., Zhou, Y., GRUBB, A. O., & Gan, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371641 · Cited by 112
Li, X., & Buxbaum, J. N. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-79 · Cited by 104
“Ab can be degraded by a number of proteases including angiotensin converting enzyme (ACE) [79,80], Cathepsin B [81], endothelin converting enzymes (ECE) [82], glutamate carboxypeptidase II [83], matrix metalloproteinases (MMP-2/gelatinase A [84], MMP-9/gelatinase B [85,86]), plasmin [87,88], neprilysin”
BackgroundLiu, R., Groen, T. V., Katre, A. K., Cao, D., Kadisha, I., Ballinger, C. A., Wang, L., Carroll, S. L., & Li, L. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.06.003 · Cited by 97
Stomrud, E., Björkqvist, M., Janciauskiene, S. M., Minthon, L., & Hansson, O. (2010) · Alzheimer s Research & Therapy · doi:10.1186/alzrt44 · Cited by 107
“Moreover, MMP-3 and MMP-9 can cleave and degrade Ab fibrils [8,13].”
BackgroundRecent therapeutic strategies targeting beta amyloid and tauopathies in Alzheimer's disease
Madav, Y., Wairkar, S., & Prabhakar, B. R. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.01.004 · Cited by 122
Matrix Metalloproteinases, New Insights into the Understanding of Neurodegenerative Disorders
Kim, Y.-S., & Joh, T. H. (2012) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2012.20.2.133 · Cited by 103
“MMPs may directly de-grade Aβ resulting in reduction in Aβ deposit (Yan et al., 2006; Miners et al., 2008).”
BackgroundLu, X.-Y., Huang, S., Chen, Q.-B., Zhang, D.-P., Li, W., Ao, R., Leung, F. C.-Y., Zhang, Z.-M., Huang, J.-S., Tang, Y., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2315106 · Cited by 98
Hernández‐Guillamón, M., Martínez-Sáez, E. A., Delgado, P., Domingues‐Montanari, S., Boada, C., Peñalba, A., Boada, M., Pagola, J., Maisterra, O., Rodríguez‐Luna, D., et al. (2011) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00512.x · Cited by 97
“Despite the ability to degrade a range of protein substrates, as certain components of the basal lamina, MMP-2 and MMP-9 can proteolyse different Ab peptides in vitro (4, 7, 10, 20, 32).”
BackgroundMolecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment
Knezevic, D., & Mizrahi, R. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.05.007 · Cited by 97
“It has been proposed that microglia attempt to clear the brain of amyloid through the phagocytosis of Aβ and secretion of proteolytic enzymes that degrade Aβ (Leissring et al., 2003; Yan et al., 2006).”
Multiple functions of insulin-degrading enzyme: a metabolic crosslight?
Tundo, G. R., Sbardella, D., Ciaccio, C., Grasso, G., Gioia, M., Coletta, A., Polticelli, F., Pierro, D. D., Milardi, D., Endert, P. V., et al. (2017) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2017.1337707 · Cited by 106
“Cytosolic enzymes capable of degrading nontoxic oligomers likely do not exist and in the extracellular space only the MMP-9 was described to be able to partially degrade amyloid plaques (Yan et al. 2006).”
BackgroundMulder, S. D., Veerhuis, R., Blankenstein, M. A., & Nielsen, H. M. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.11.001 · Cited by 97
Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges
Zipfel, P., Rochais, C., Baranger, K., Rivera, S., & Dallemagne, P. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00352 · Cited by 94
Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia
Weekman, E. M., & Wilcock, D. M. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150759 · Cited by 106
Rivera, S., García-González, L., Khrestchatisky, M., & Baranger, K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03178-2 · Cited by 111
Liao, M.-C., & Van Nostrand, W. E. (2010) · Biochemistry · doi:10.1021/bi901994d · Cited by 92
“MMP9, like MT1-MMP, cleaves between residues Ala30-Ile31 (37).”
BackgroundMethodInfluentialA New Face for Old Antibiotics: Tetracyclines in Treatment of Amyloidoses
Stoilova, T., Colombo, L., Forloni, G., Tagliavini, F., & Salmona, M. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400161p · Cited by 97
García-González, L., Pilat, D., Baranger, K., & Rivera, S. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00244 · Cited by 88
“…with Aβ-degrading, activity, such as MMP-2, MMP-3, MMP-7 and MMP-9 (Roher et al., 1994; Backstrom et al., 1996; Deb et al., 2003; White et al., 2006; Yan et al., 2006; Yin et al., 2006; Hernandez-Guillamon et al., 2010, 2015; Liao and Van Nostrand, 2010; Py et al., 2014; Brkic et al., 2015;…”
BackgroundMizoguchi, H., Takuma, K., Fukuzaki, E., Ibi, D., Someya, E., Akazawa, K., Alkam, T., Tsunekawa, H., Mouri, A., Noda, Y., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.154724 · Cited by 87
“Notably, MMP-9 was reported to cleave insoluble A in vitro (Yan et al., 2006).”
BackgroundInfluentialECM in brain aging and dementia
Morawski, M., Filippov, M., Tzinia, A., Tsilibary, E., & Vargova, L. (2014) · Progress in Brain Research · doi:10.1016/b978-0-444-63486-3.00010-4 · Cited by 84
“, 2008) and in reactive astrocytes surrounding amyloid plaques (Baig et al., 2008; Yan et al., 2006; Yin et al., 2006), suggesting a local tissue response to plaque accumulation.”
InfluentialMatrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines
Stawarski, M., Stefaniuk, M., & Włodarczyk, J. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00068 · Cited by 87
“The ability of MMP9 to cleave β-amyloid peptide is particularly interesting because an increase in MMP-9 expression was observed in Alzheimer’s disease patients by several research groups (Backstrom et al., 1996; Yan et al., 2006; Mizoguchi et al., 2011a; Filippov and Dityatev, 2012).”
BackgroundHollow core of Alzheimer’s Aβ42 amyloid observed by cryoEM is relevant at physiological pH
Miller, Y., Ma, B., Tsai, C.-J., & Nussinov, R. (2010) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1004704107 · Cited by 84
“(2009) Comparison of Alzheimer Abeta(1-40) and Abeta(1-42)”
BackgroundInfluentialMMP-9 Sheds the β2 Integrin Subunit (CD18) from Macrophages
Vaisar, T., Kassim, S. Y., Gomez, I. G., Green, P. S., Hargarten, S., Gough, P. J., Parks, W. C., Wilson, C. L., Raines, E. W., & Heinecke, J. W. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m800449-mcp200 · Cited by 91
“This raises the intriguing possibility that MMP-9 might reduce cerebral amyloid burden by two complementary mechanisms: by impairing production and by increasing the degradation of amyloid- peptide (63, 80, 82, 83).”
BackgroundAmyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders
Batarseh, Y. S., Duong, Q.-V., Mousa, Y. M., Rihani, S. B. A., Elfakhri, K. H., & Kaddoumi, A. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17030338 · Cited by 82
“Beside transport proteins, astrocytes mediate the clearance of Aβ directly by endocomal-lysosomal pathways subjecting Aβ to degradation by a variety of degrading enzymes such as insulin-degrading enzyme (IDE) and neprilysin (NEP) that are only effective on the degradation of Aβ monomers [52,53], while matrix metallopr…”
BackgroundMatrix metalloproteinases in Alzheimer’s disease and concurrent cerebral microbleeds.
Duits, F. H., Hernandez-Guillamon, M., Montaner, J., Goos, J. D. C., Montañola, A., Wattjes, M. P., Barkhof, F., Scheltens, P., Teunissen, C. E., & van der Flier, W. M. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-143186 · Cited by 92
“Post-hoc tests showed higher CSF MMP10 levels in AD patients compared to controls (median [IQR] 25 [16–35] versus 13 [10–20] pg/mL, p= 0.”
InfluentialProfiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia
Lorenzl, S., Büerger, K., Hampel, H. J., & Beal, M. F. (2007) · International Psychogeriatrics · doi:10.1017/s1041610207005790 · Cited by 96
Tzeng, T.-T., Chen, C.-C., Chen, C., Tsay, H.-J., Lee, L., Chen, W.-P., Shen, C.-C., & Shiao, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020598 · Cited by 86
“It is well established that plaques are visible in 6 month old APP/PS1 mice [23].”
BackgroundMethodZhang, K., Li, T. X., Liu, L., Feng, Y., Dong, Y.-B., Li, B., Shang, D., Fang, W., Cao, Y., & Chen, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072744 · Cited by 89
“Aβ deposition and limit AD process [12,13], thus performing a neuroprotective role in AD.”
BackgroundRestored degradation of the Alzheimer’s amyloid‐β peptide by targeting amyloid formation
Crouch, P. J., Tew, D. J., Du, T., Nguyen, D., Caragounis, A., Filiz, G., Blake, R. E., Trounce, I. A., Soon, C. P. W., Laughton, K. M., et al. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05870.x · Cited by 88
“Consistent with previous reports (Roher et al. 1994; Backstrom et al. 1996; Yan et al. 2006) surface enhanced laser desorption ionisation time of flight mass spectrometry analysis showed MMP-mediated generation of an Ab fragment with a mass equal to Ab1–34 (Ab34), indicating cleavage between Ab residues leu34 and met3…”
ResultCrouch, P. J., White, A. R., & Bush, A. I. (2007) · FEBS Journal · doi:10.1111/j.1742-4658.2007.05918.x · Cited by 78
Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression
Basudhar, D., Somasundaram, V., de Oliveira, G. A., Kesarwala, A. H., Heinecke, J. L., Cheng, R. Y. S., Glynn, S. A., Ambs, S., Wink, D. A., & Ridnour, L. A. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6813 · Cited by 92
“HIF-1a stabilization by NO activates a number of signaling pathways mediated by the promoter hypoxia response element (HRE) to confer survival and growth advantage, angiogenesis, wound repair, and tumor development (130, 163).”
BackgroundMatrix Metalloproteases as Influencers of the Cells’ Social Media
Young, D. W., Das, N., Anowai, A., & Dufour, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163847 · Cited by 86
Quan, Q.-K., Wang, J., Li, X., & Wang, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059155 · Cited by 77
“Ab is degraded by many proteases, including neprilysin [43,44], endothelin-converting enzyme [45,46], angiotensin-converting enzyme [47], plasminogen activator [48,49], and matrix metalloproteinase-9 [50].”
BackgroundNeuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice
Fragkouli, A., Tsilibary, E. C., & Tzinia, A. K. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.06.021 · Cited by 90
Aspects of β-Amyloid as a Biomarker for Alzheimer's Disease
Andréasson, U., Portelius, E., Andersson, M. E., Blennow, K., & Zetterberg, H. (2007) · Biomarkers in Medicine · doi:10.2217/17520363.1.1.59 · Cited by 74
Son, S. M., Song, H., Byun, J., Park, K. S., Jang, H. C., Park, Y. J., & Mook‐Jung, I. (2012) · Diabetes · doi:10.2337/db11-1735 · Cited by 81
Self-citationDisease-Modifying Therapies in Alzheimer???s Disease
ll, M. H., Berger, T., & Heneka, M. T. (2006) · Drugs · doi:10.2165/00003495-200666160-00004 · Cited by 95
Lacoste, B., Tong, X.-K., Lahjouji, K., Couture, R., & Hamel, E. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-57 · Cited by 73
“As MMP9 is involved in both BBB integrity and Aβ clearance [40-43], its protein levels were also measured.”
Metadata
- Authors
- Yan, P., Hu, X., Song, H., Yin, K., Bateman, R. J., Cirrito, J. R., Xiao, Q., Hsu, F. F., Turk, J. W., Xu, J., Hsu, C. Y., Holtzman, D. M., & Lee, J.-M.
- Affiliations
- Washington University in St. Louis (US)
- Taipei Medical University (TW)
- Corresponding author
- Lee, Jin-Moo
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-08
- Volume
- 281
- Issue
- 34
- Pages
- 24566-24574
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2097292535
- Cited by
- 380
- References
- 58
- Citations by year
- 2026: 16 · 2025: 9 · 2024: 16 · 2023: 21 · 2022: 13 · 2021: 21 · 2020: 30 · 2019: 13 · 2018: 19 · 2017: 28 · 2016: 11 · 2015: 26 · 2014: 28 · 2013: 17 · 2012: 26
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p60dk020579-35, 5p41rr000954-34, DK20579, P60-DK-20579, DK56341, P41 RR00954, AG13956)
- U.S. Public Health Service (P60-DK-20579, P41‐RR‐00954, P30‐DK‐56341)
- National Institute on Aging (L30 AG024455, K08AG027091, AG13956)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60-DK20579, P30-DK56341, P30DK056341)
- National Institute of Neurological Disorders and Stroke (NS048283, R01NS048283)
- National Center for Research Resources (P41 RR-00954)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- MMP-9, amyloid-beta fibrils, amyloid plaques, Alzheimer's disease, amyloid beta degradation, proteolytic cleavage sites, APP/PS1 mice, astrocytes, plaque clearance, thioflavin T staining
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Humans, Hydrolysis, Immunohistochemistry, Mice, Transgenic, Mass Spectrometry, Substrate Specificity, Amyloid beta-Peptides, Matrix Metalloproteinase 9, Mice, Plaque, Amyloid
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