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The Journal of Neuroscience, February 15, 2001, 21(4):1179-1188
 -Amyloid Stimulation of Microglia and Monocytes Results in
TNF -Dependent Expression of Inducible Nitric Oxide Synthase and
Neuronal Apoptosis
Colin K.
Combs,
J. Colleen
Karlo,
Shih-Chu
Kao, and
Gary
E.
Landreth
Alzheimer Research Laboratory, Departments of Neurosciences and
Neurology, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106
Reactive microglia associated with the  -amyloid plaques in
Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar
-amyloid peptides activate a tyrosine kinase-based signaling
response in primary mouse microglia and the human monocytic cell line,
THP-1, resulting in production of neurotoxic secretory products,
proinflammatory cytokines, and reactive oxygen species. We report that
most of the amyloid-induced tyrosine kinase activity was stimulated
after activation of Src family members such as Lyn. However,
transduction of the signaling response required for increased
production of the cytokines TNF and IL1- was mediated by the
nonreceptor tyrosine kinase, Syk. Additionally, -amyloid stimulated
an NF B-dependent pathway in parallel that was required for cytokine
production. Importantly, TNF generated by the monocytes and
microglia was responsible for the majority of the neuorotoxic activity
secreted by these cells after -amyloid stimulation but must act in
concert with other factors elaborated by microglia to elicit neuronal
death. Moreover, we observed that the neuronal loss was apoptotic in
nature and involved increased neuronal expression of inducible nitric
oxide synthase and subsequent peroxynitrite production. Selective
inhibitors of inducible nitric oxide synthase effectively protected
cells from toxicity associated with the microglial and monocytic
secretory products. This study demonstrates a functional linkage
between -amyloid-dependent activation of microglia and several
characteristic markers of neuronal death occurring in Alzheimer's
disease brains.
Key words:
Alzheimer's disease; -amyloid; microglia; THP-1
monocytes; signal transduction; tyrosine kinase; Lyn; Syk; inflammation; neurotoxicity; apoptosis; nitric oxide; nitrotyrosine; peroxynitrite; TNF; cytokines
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141179-10$05.00/0
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|
|
|
|
|
|
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173(6):
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181(10):
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|
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4201 - 4212.
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|
|
|
|
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Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury
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325(1):
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|
|
|
|
|
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27(46):
12555 - 12564.
[Abstract]
[Full Text]
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|
|
|
|
|
|
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September 1, 2007;
92(5):
807 - 811.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
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21(9):
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|
|
|
|
|
|
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Z. S. Tan, A. S. Beiser, R. S. Vasan, R. Roubenoff, C. A. Dinarello, T. B. Harris, E. J. Benjamin, R. Au, D. P. Kiel, P. A. Wolf, et al.
Inflammatory markers and the risk of Alzheimer disease: The Framingham Study
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68(22):
1902 - 1908.
[Abstract]
[Full Text]
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|
|
|
|
|
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H. B. Choi, J. K. Ryu, S. U. Kim, and J. G. McLarnon
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27(18):
4957 - 4968.
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|
|
|
|
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R. Fan, F. Xu, M. L. Previti, J. Davis, A. M. Grande, J. K. Robinson, and W. E. Van Nostrand
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27(12):
3057 - 3063.
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[Full Text]
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|
|
|
|
|
|
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S. Franciosi, J. K. Ryu, H. B. Choi, L. Radov, S. U. Kim, and J. G. McLarnon
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|
|
|
|
|
|
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|
|
|
|
|
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281(30):
20842 - 20850.
[Abstract]
[Full Text]
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|
|
|
|
|
|
|
Y.-J. Zhang, Y.-F. Xu, Y.-H. Liu, J. Yin, H.-L. Li, Q. Wang, and J.-Z. Wang
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|
|
|
|
|
|
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26(17):
4644 - 4648.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Qin, C. Colin, I. Hinners, A. Gervais, C. Cheret, and M. Mallat
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26(12):
3345 - 3356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Chen, Y. Zhou, S. Mueller-Steiner, L.-F. Chen, H. Kwon, S. Yi, L. Mucke, and L. Gan
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280(48):
40364 - 40374.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Cicero and K. Herrup
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25(42):
9658 - 9668.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Cordle, J. Koenigsknecht-Talboo, B. Wilkinson, A. Limpert, and G. Landreth
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J. Biol. Chem.,
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280(40):
34202 - 34209.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Koenigsknecht-Talboo and G. E. Landreth
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J. Neurosci.,
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25(36):
8240 - 8249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Giri, V. Rajagopal, S. Shahi, B. V. Zlokovic, and V. K. Kalra
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Am J Physiol Cell Physiol,
August 1, 2005;
289(2):
C264 - C276.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Zhan, P. Fenik, D. Pratico, and S. C. Veasey
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Am. J. Respir. Crit. Care Med.,
June 15, 2005;
171(12):
1414 - 1420.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Floden, S. Li, and C. K. Combs
{beta}-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor {alpha} and NMDA Receptors
J. Neurosci.,
March 9, 2005;
25(10):
2566 - 2575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Cordle and G. Landreth
3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate {beta}-Amyloid-Induced Microglial Inflammatory Responses
J. Neurosci.,
January 12, 2005;
25(2):
299 - 307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Twig, S. A. Graf, M. A. Messerli, P. J. S. Smith, S. H. Yoo, and O. S. Shirihai
Synergistic amplification of {beta}-amyloid- and interferon-{gamma}-induced microglial neurotoxic response by the senile plaque component chromogranin A
Am J Physiol Cell Physiol,
January 1, 2005;
288(1):
C169 - C175.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-F. Liao, B.-J. Wang, H.-T. Cheng, L.-H. Kuo, and M. S. Wolfe
Tumor Necrosis Factor-{alpha}, Interleukin-1{beta}, and Interferon-{gamma} Stimulate {gamma}-Secretase-mediated Cleavage of Amyloid Precursor Protein through a JNK-dependent MAPK Pathway
J. Biol. Chem.,
November 19, 2004;
279(47):
49523 - 49532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Novarino, C. Fabrizi, R. Tonini, M. A. Denti, F. Malchiodi-Albedi, G. M. Lauro, B. Sacchetti, S. Paradisi, A. Ferroni, P. M. Curmi, et al.
Involvement of the Intracellular Ion Channel CLIC1 in Microglia-Mediated {beta}-Amyloid-Induced Neurotoxicity
J. Neurosci.,
June 9, 2004;
24(23):
5322 - 5330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Gan, S. Ye, A. Chu, K. Anton, S. Yi, V. A. Vincent, D. von Schack, D. Chin, J. Murray, S. Lohr, et al.
Identification of Cathepsin B as a Mediator of Neuronal Death Induced by A{beta}-activated Microglial Cells Using a Functional Genomics Approach
J. Biol. Chem.,
February 13, 2004;
279(7):
5565 - 5572.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Suzuki, I. Hide, K. Ido, S. Kohsaka, K. Inoue, and Y. Nakata
Production and Release of Neuroprotective Tumor Necrosis Factor by P2X7 Receptor-Activated Microglia
J. Neurosci.,
January 7, 2004;
24(1):
1 - 7.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. B. El Khoury, K. J. Moore, T. K. Means, J. Leung, K. Terada, M. Toft, M. W. Freeman, and A. D. Luster
CD36 Mediates the Innate Host Response to {beta}-Amyloid
J. Exp. Med.,
June 16, 2003;
197(12):
1657 - 1666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Giri, S. K. Selvaraj, and V. K. Kalra
Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA
J. Immunol.,
May 15, 2003;
170(10):
5281 - 5294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. K. Parvathenani, S. Tertyshnikova, C. R. Greco, S. B. Roberts, B. Robertson, and R. Posmantur
P2X7 Mediates Superoxide Production in Primary Microglia and Is Up-regulated in a Transgenic Mouse Model of Alzheimer's Disease
J. Biol. Chem.,
April 4, 2003;
278(15):
13309 - 13317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Bamberger, M. E. Harris, D. R. McDonald, J. Husemann, and G. E. Landreth
A Cell Surface Receptor Complex for Fibrillar beta -Amyloid Mediates Microglial Activation
J. Neurosci.,
April 1, 2003;
23(7):
2665 - 2674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Moore, J. El Khoury, L. A. Medeiros, K. Terada, C. Geula, A. D. Luster, and M. W. Freeman
A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of beta -Amyloid
J. Biol. Chem.,
November 27, 2002;
277(49):
47373 - 47379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Wei, D. D. Norton, X. Wang, and J. W. Kusiak
A{beta} 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis
Brain,
September 1, 2002;
125(9):
2036 - 2043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. Bamberger and G. E. Landreth
Inflammation, Apoptosis, and Alzheimer's Disease
Neuroscientist,
June 1, 2002;
8(3):
276 - 283.
[Abstract]
[PDF]
|
|
|
|
|
|
|
W. Wei, X. Wang, and J. W. Kusiak
Signaling Events in Amyloid beta -Peptide-induced Neuronal Death and Insulin-like Growth Factor I Protection
J. Biol. Chem.,
May 10, 2002;
277(20):
17649 - 17656.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Xie, M. Wei, T. E. Morgan, P. Fabrizio, D. Han, C. E. Finch, and V. D. Longo
Peroxynitrite Mediates Neurotoxicity of Amyloid beta -Peptide1-42- and Lipopolysaccharide-Activated Microglia
J. Neurosci.,
May 1, 2002;
22(9):
3484 - 3492.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Sousa, S. Du Yan, R. Fernandes, A. Guimaraes, D. Stern, and M. J. Saraiva
Familial Amyloid Polyneuropathy: Receptor for Advanced Glycation End Products-Dependent Triggering of Neuronal Inflammatory and Apoptotic Pathways
J. Neurosci.,
October 1, 2001;
21(19):
7576 - 7586.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Robertson, J.-M. Beaulieu, M. M. Doroudchi, H. D. Durham, J.-P. Julien, and W. E. Mushynski
Apoptotic death of neurons exhibiting peripherin aggregates is mediated by the proinflammatory cytokine tumor necrosis factor-{alpha}
J. Cell Biol.,
October 15, 2001;
155(2):
217 - 226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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