Characterization of Neutral Proteinases from Alzheimer‐Affected and Control Brain Specimens: Identification of Calcium‐Dependent Metalloproteinases from the Hippocampus

Backstrom, Jon R.; Miller, Carol A.; Tökés, Zoltán A.

doi:10.1111/j.1471-4159.1992.tb09352.x

Cited by 112 publications

(90 citation statements)

References 30 publications

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“…Finally, given the ability of macrophages to degrade both nonfibrillar as well as fibrillar A␤ plaques/ deposits, along with the specific A␤ peptides produced after incubation of A␤42 with macrophages or MCM, we examined the possible role of known A␤-degrading enzymes, but especially MMP-9, which has in contrast to neprilysin and insulindegrading enzyme, recently been shown to degrade fibrillar A␤42 and is known to be secreted from various cells including macrophages, astrocytes, and microglia (Gottschall et al, 1995;Muir et al, 2002). Additionally, the expression of MMP-9 has also been observed to be increased in the brain of AD patients (Backstrom et al, 1992;Lorenzl et al, 2003), indicating that MMP-9 may play an important role in AD pathology. We observed that cellular MMP-9 expression measured by IHC was indeed apoE isoform-dependent (E2 Ͼ E3 Ͼ E4) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Zhao

Su²,

Bales³

et al. 2009

J. Neurosci.

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Recent studies suggest that bone marrow-derived macrophages can effectively reduce ␤-amyloid (A␤) deposition in brain. To further elucidate the mechanisms by which macrophages degrade A␤, we cultured murine macrophages on top of A␤ plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP 717VϾF mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble A␤ in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of A␤ degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading A␤ than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of A␤ was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with A␤-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3-or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in A␤ degradation by macrophages. These apoE isoform-dependent effects of macrophages on A␤ degradation suggest a novel "peripheral" mechanism for A␤ clearance from brain that may also, in part, explain the isoformdependent effects of apoE in determining the genetic risk for Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Zhao

Su²,

Bales³

et al. 2009

J. Neurosci.

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“…A number of reports have indicated that MMPs are involved in the pathogenesis of a wide range of diseases and disorders of the CNS, including neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and progressive supranuclear cerebral palsy [10][11][12][13][14] as well as stroke injuries [15]. It has been suggested that this class of extracellular proteases may be appropriate molecular targets to reduce secondary tissue degeneration and improve functional outcome [7,16].…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury

Buss¹,

Pech²,

Noth³

et al. 2006

Akt Neurol

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Background: Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidases that degrade the extracellular matrix and other extracellular proteins. Studies in experimental animals demonstrate that MMPs play a number of roles in the detrimental as well as in the beneficial events after spinal cord injury (SCI). In the present correlative investigation, the expression pattern of several MMPs and their inhibitors has been investigated in the human spinal cord.

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“…In addition, they play an important role in the fetal development, inflammatory cell migration and wound healing [27]. Under non-physiological conditions, MMPs are involved in tumour cell proliferation and dissemination [28] and in the pathophysiology of tissue-destructive diseases such as arthritis [29], multiple sclerosis [30] and central nervous system disorders [31]. MMPs, such as gelatinase B and collagenase, are mainly stored in the specific granules, whereas serine proteinases, such as elastase, proteinase 3 and cathepsin G, are located in azurophilic granules.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

Moţa¹,

Moldovan²,

Călugăru³

et al. 2004

Scand J Immunol

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Human natural killer (NK) cells express low-affinity Fc immunoglobulin G (IgG) receptor (FcgRIIIA/CD16). The binding of monomeric IgG (mIgG) and F(ab 0 ) 2 fragments of 3G8 anti-CD16 monoclonal antibody (mAb) to FcgRIIIA was investigated by flow cytometry. Over 90% of NK cells bound endogenous IgG, and during incubation at 37 C, the FcgRIIIA occupancy decreased slowly. Approximately 90% of NK cells bind mIgG or F(ab 0 ) 2 fragments of 3G8 anti-CD16 mAb. The calculated half-time (T 1/2 ) of in vitro mIgG dissociation from FcgRIIIA was 130 min. By cross-linking the mIgG ligand with F(ab 0 ) 2 fragments of anti-human IgG antibody, the T 1/2 decreases to 85 min. In kinetics study, it has been shown that 125 I-mIgG bound to FcgRIIIA is slowly released in the culture supernatant, maybe eluted at acid pH, or partially internalized and degraded. The binding of IgG to FcgRIIIA was increased by 53.8% on cells cultured in the presence of RU36156, a matrix metalloproteinase (MMP) inhibitor. Furthermore, an increase in phosphorylation of Lyn tyrosine kinase, after cross-linking of mIgG-FcgRIIIA complex, was observed on NK cells treated with RU36156. When the FcgRIIIA was occupied by mIgG, the capacity of NK cells to kill K562 target cells was decreased by RU36156, because the MMP inhibitor protects CD16 from proteolysis. Our data demonstrate that binding of mIgG to human NK cells is followed by ligand dissociation and/or internalization, enzymatic degradation and exocytosis. The RU36156 MMP inhibitor protects FcgRIIIA from cleavage, augments NK-cell activation and may interfere in their killing capacity.

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Characterization of Neutral Proteinases from Alzheimer‐Affected and Control Brain Specimens: Identification of Calcium‐Dependent Metalloproteinases from the Hippocampus

Cited by 112 publications

References 30 publications

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury

Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

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