 |
 Previous Article | Next Article 
Volume 16, Number 24,
Issue of December 15, 1996
pp. 7910-7919
Copyright ©1996 Society for Neuroscience
Matrix Metalloproteinase-9 (MMP-9) Is Synthesized in Neurons of
the Human Hippocampus and Is Capable of Degrading the Amyloid-
Peptide (1-40)
Received Feb. 7, 1996; revised Sept. 3, 1996; accepted Oct. 4, 1996.
Jon R. Backstrom1,
Giselle P. Lim2,
Michael J. Cullen2, and
Zoltán A. Tökés1, 3
Departments of 1 Biochemistry and Molecular Biology and
2 Cell and Neurobiology, and the 3 USC/Norris
Comprehensive Cancer Center, School of Medicine, University of Southern
California, Los Angeles, California 90089
We reported earlier that the levels of Ca2+-dependent
metalloproteinases are increased in Alzheimer's disease (AD)
specimens, relative to control specimens. Here we show that these
enzymes are forms of the matrix metalloproteinase MMP-9 (EC3.4.24.35) and are expressed in the human hippocampus. Affinity-purified antibodies to MMP-9 labeled pyramidal neurons, but not granular neurons
or glial cells. MMP-9 mRNA is expressed in pyramidal neurons, as
determined with digoxigenin-labeled MMP-9 riboprobes, and the presence
of this mRNA is confirmed with reverse transcriptase PCR. The cellular
distribution of MMP-9 is altered in AD because 76% of the total 100 kDa enzyme activity is found in the soluble fraction of control
specimens, whereas only 51% is detectable in the same fraction from AD
specimens. The accumulated 100 kDa enzyme from AD brain is latent and
can be converted to an active form with aminophenylmercuric
acetate.
MMP-9 also is detected in close proximity to extracellular amyloid
plaques. Because a major constituent of plaques is the 4 kDa
 -amyloid peptide, synthetic A1-40 was incubated with
activated MMP-9. The enzyme cleaves the peptide at several sites,
predominantly at Leu34-Met35 within the
membrane-spanning domain. These results establish that neurons have the
capacity to synthesize MMP-9, which, on activation, may degrade
extracellular substrates such as -amyloid. Because the latent form
of MMP-9 accumulates in AD brain, it is hypothesized that the lack of
enzyme activation contributes to the accumulation of insoluble
-amyloid peptides in plaques.
Key words:
matrix metalloproteinases;
Alzheimer's
disease;
amyloid cleavage;
amyloid plaques;
gelatinase;
protease
activation
This article has been cited by other articles:
|
|
|
|
 
M.-C. Liao, M. Ahmed, S. O. Smith, and W. E. Van Nostrand
Degradation of Amyloid {beta} Protein by Purified Myelin Basic Protein
J. Biol. Chem.,
October 16, 2009;
284(42):
28917 - 28925.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Mizoguchi, K. Takuma, E. Fukuzaki, D. Ibi, E. Someya, K.-h. Akazawa, T. Alkam, H. Tsunekawa, A. Mouri, Y. Noda, et al.
Matrix Metalloprotease-9 Inhibition Improves Amyloid {beta}-Mediated Cognitive Impairment and Neurotoxicity in Mice
J. Pharmacol. Exp. Ther.,
October 1, 2009;
331(1):
14 - 22.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Vaisar, S. Y. Kassim, I. G. Gomez, P. S. Green, S. Hargarten, P. J. Gough, W. C. Parks, C. L. Wilson, E. W. Raines, and J. W. Heinecke
MMP-9 Sheds the {beta}2 Integrin Subunit (CD18) from Macrophages
Mol. Cell. Proteomics,
May 1, 2009;
8(5):
1044 - 1060.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Zhao, S. Lin, K. R. Bales, V. Gelfanova, D. Koger, C. DeLong, J. Hale, F. Liu, J. M. Hunter, and S. M. Paul
Macrophage-Mediated Degradation of {beta}-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism
J. Neurosci.,
March 18, 2009;
29(11):
3603 - 3612.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Cohen, C. Wuillemin, O. Irion, and P. Bischof
Regulation of MMP-9 by p53 in first trimester cytotrophoblastic cells
Hum. Reprod.,
October 1, 2008;
23(10):
2273 - 2281.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Vetrivel, X. Zhang, X. Meckler, H. Cheng, S. Lee, P. Gong, K. O. Lopes, Y. Chen, N. Iwata, K.-J. Yin, et al.
Evidence That CD147 Modulation of {beta}-Amyloid (A{beta}) Levels Is Mediated by Extracellular Degradation of Secreted A{beta}
J. Biol. Chem.,
July 11, 2008;
283(28):
19489 - 19498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Donnelly, A. Caragounis, T. Du, K. M. Laughton, I. Volitakis, R. A. Cherny, R. A. Sharples, A. F. Hill, Q.-X. Li, C. L. Masters, et al.
Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-{beta} Peptide
J. Biol. Chem.,
February 22, 2008;
283(8):
4568 - 4577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-J. Yin, J. R. Cirrito, P. Yan, X. Hu, Q. Xiao, X. Pan, R. Bateman, H. Song, F.-F. Hsu, J. Turk, et al.
Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-beta Peptide Catabolism
J. Neurosci.,
October 25, 2006;
26(43):
10939 - 10948.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Yan, X. Hu, H. Song, K. Yin, R. J. Bateman, J. R. Cirrito, Q. Xiao, F. F. Hsu, J. W. Turk, J. Xu, et al.
Matrix Metalloproteinase-9 Degrades Amyloid-beta Fibrils in Vitro and Compact Plaques in Situ
J. Biol. Chem.,
August 25, 2006;
281(34):
24566 - 24574.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. R. White, T. Du, K. M. Laughton, I. Volitakis, R. A. Sharples, M. E. Xilinas, D. E. Hoke, R. M. D. Holsinger, G. Evin, R. A. Cherny, et al.
Degradation of the Alzheimer Disease Amyloid beta-Peptide by Metal-dependent Up-regulation of Metalloprotease Activity
J. Biol. Chem.,
June 30, 2006;
281(26):
17670 - 17680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Walker, J. Link, L.-F. Lue, J. E. Dalsing-Hernandez, and B. E. Boyes
Gene expression changes by amyloid {beta} peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes
J. Leukoc. Biol.,
March 1, 2006;
79(3):
596 - 610.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Y. Sung, S. M. Park, C.-H. Lee, J. W. Um, H. J. Lee, J. Kim, Y. J. Oh, S.-T. Lee, S. R. Paik, and K. C. Chung
Proteolytic Cleavage of Extracellular Secreted {alpha}-Synuclein via Matrix Metalloproteinases
J. Biol. Chem.,
July 1, 2005;
280(26):
25216 - 25224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Glatzel, M. H. Mohajeri, R. Poirier, R. M. Nitsch, P. Schwarz, B. Lu, and A. Aguzzi
No influence of amyloid-{beta}-degrading neprilysin activity on prion pathogenesis
J. Gen. Virol.,
June 1, 2005;
86(6):
1861 - 1867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. O. Lee, J. L. Kang, and Y. H. Chong
The Amyloid-{beta} Peptide Suppresses Transforming Growth Factor-{beta}1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells
J. Biol. Chem.,
March 4, 2005;
280(9):
7845 - 7853.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Nagai, K. Yamada, M. Yoshimura, K. Ishikawa, Y. Miyamoto, K. Hashimoto, Y. Noda, A. Nitta, and T. Nabeshima
From The Cover: The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release
PNAS,
March 9, 2004;
101(10):
3650 - 3655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Eckman, M. Watson, L. Marlow, K. Sambamurti, and C. B. Eckman
Alzheimer's Disease beta -Amyloid Peptide Is Increased in Mice Deficient in Endothelin-converting Enzyme
J. Biol. Chem.,
January 17, 2003;
278(4):
2081 - 2084.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. J. Noble, F. Donovan, T. Igarashi, S. Goussev, and Z. Werb
Matrix Metalloproteinases Limit Functional Recovery after Spinal Cord Injury by Modulation of Early Vascular Events
J. Neurosci.,
September 1, 2002;
22(17):
7526 - 7535.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-H. Suh and F. Checler
Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Pharmacol. Rev.,
September 1, 2002;
54(3):
469 - 525.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. J. Salles and S. Strickland
Localization and Regulation of the Tissue Plasminogen Activator-Plasmin System in the Hippocampus
J. Neurosci.,
March 15, 2002;
22(6):
2125 - 2134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Szklarczyk, J. Lapinska, M. Rylski, R. D. G. McKay, and L. Kaczmarek
Matrix Metalloproteinase-9 Undergoes Expression and Activation during Dendritic Remodeling in Adult Hippocampus
J. Neurosci.,
February 1, 2002;
22(3):
920 - 930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-T. Khuth, H. Akaoka, A. Pagenstecher, O. Verlaeten, M.-F. Belin, P. Giraudon, and A. Bernard
Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression
J. Virol.,
September 1, 2001;
75(17):
8268 - 8282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. O. Evert, I. R. Vogt, C. Kindermann, L. Ozimek, R. A. I. de Vos, E. R. P. Brunt, I. Schmitt, T. Klockgether, and U. Wullner
Inflammatory Genes Are Upregulated in Expanded Ataxin-3-Expressing Cell Lines and Spinocerebellar Ataxia Type 3 Brains
J. Neurosci.,
August 1, 2001;
21(15):
5389 - 5396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pagenstecher, A. K. Stalder, C. L. Kincaid, B. Volk, and I. L. Campbell
Regulation of Matrix Metalloproteinases and Their Inhibitor Genes in Lipopolysaccharide-Induced Endotoxemia in Mice
Am. J. Pathol.,
July 1, 2000;
157(1):
197 - 210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Creange, T. Sharshar, T. Planchenault, C. Christov, F. Poron, J.-C. Raphael, and R. K. Gherardi
Matrix metalloproteinase-9 is increased and correlates with severity in Guillain-Barre syndrome
Neurology,
November 1, 1999;
53(8):
1683 - 1683.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. A. Frautschy, D. L. Horn, J. J. Sigel, M. E. Harris-White, J. J. Mendoza, F. Yang, T. C. Saido, and G. M. Cole
Protease Inhibitor Coinfusion with Amyloid beta -Protein Results in Enhanced Deposition and Toxicity in Rat Brain
J. Neurosci.,
October 15, 1998;
18(20):
8311 - 8321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Mohan, W. B. Rinehart, P. Bargagna-Mohan, and M. E. Fini
Gelatinase B/lacZ Transgenic Mice, a Model for Mapping Gelatinase B Expression during Developmental and Injury-related Tissue Remodeling
J. Biol. Chem.,
October 2, 1998;
273(40):
25903 - 25914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Tsirka, T. H. Bugge, J. L. Degen, and S. Strickland
Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin
PNAS,
September 2, 1997;
94(18):
9779 - 9781.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Eckman, D. K. Reed, and C. B. Eckman
Degradation of the Alzheimer's Amyloid beta Peptide by Endothelin-converting Enzyme
J. Biol. Chem.,
June 29, 2001;
276(27):
24540 - 24548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shirotani, S. Tsubuki, N. Iwata, Y. Takaki, W. Harigaya, K. Maruyama, S. Kiryu-Seo, H. Kiyama, H. Iwata, T. Tomita, et al.
Neprilysin Degrades Both Amyloid beta Peptides 1-40 and 1-42 Most Rapidly and Efficiently among Thiorphan- and Phosphoramidon-sensitive Endopeptidases
J. Biol. Chem.,
June 8, 2001;
276(24):
21895 - 21901.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. H. Chong, J. H. Sung, S. A. Shin, J.-H. Chung, and Y.-H. Suh
Effects of the beta -Amyloid and Carboxyl-terminal Fragment of Alzheimer's Amyloid Precursor Protein on the Production of the Tumor Necrosis Factor-alpha and Matrix Metalloproteinase-9 by Human Monocytic THP-1
J. Biol. Chem.,
June 22, 2001;
276(26):
23511 - 23517.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
