 |
 Previous Article | Next Article 
The Journal of Neuroscience, January 15, 2000, 20(2):558-567
Inflammatory Mechanisms in Alzheimer's Disease: Inhibition of
 -Amyloid-Stimulated Proinflammatory Responses and Neurotoxicity by
PPAR Agonists
Colin K.
Combs,
Derrick E.
Johnson,
J. Colleen
Karlo,
Steven B.
Cannady, and
Gary E.
Landreth
Alzheimer Research Laboratory, Departments of Neurosciences and
Neurology, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106
Alzheimer's disease (AD) is characterized by the extracellular
deposition of  -amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local
proinflammatory response with the secretion of a diverse range of
inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs)
are efficacious in reducing the incidence and risk of AD and
significantly delaying disease progression. A recently appreciated
target of NSAIDs is the ligand-activated nuclear receptor peroxisome
proliferator-activated receptor  (PPAR). PPAR is a DNA-binding
transcription factor whose transcriptional regulatory actions are
activated after agonist binding. We report that NSAIDs, drugs of the
thiazolidinedione class, and the natural ligand prostaglandin J2
act as agonists for PPAR and inhibit the -amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPAR also arrested the differentiation of monocytes into
activated macrophages. PPAR agonists were shown to inhibit the
-amyloid-stimulated expression of the cytokine genes
interleukin-6 and tumor necrosis factor  . Furthermore,
PPAR agonists inhibited the expression of cyclooxygenase-2. These
data provide direct evidence that PPAR plays a critical role in
regulating the inflammatory responses of microglia and monocytes to
-amyloid. We argue that the efficacy of NSAIDs in the treatment of
AD may be a consequence of their actions on PPAR rather than on
their canonical targets the cyclooxygenases. Importantly, the efficacy
of these agents in inhibiting a broad range of inflammatory responses
suggests PPAR agonists may provide a novel therapeutic approach to AD.
Key words:
Alzheimer's disease; -amyloid; microglia; THP-1
monocytes; signal transduction; tyrosine kinase; inflammation; neurotoxicity; PPAR; cyclooxygenase; TNF; IL-6; NSAIDs; cytokines; COX-2
Copyright © 2000 Society for Neuroscience 0270-6474/00/202558-10$05.00/0
This article has been cited by other articles:
|
|
|
|
 
R. T. Zamanian, G. Hansmann, S. Snook, D. Lilienfeld, K. M. Rappaport, G. M. Reaven, M. Rabinovitch, and R. L. Doyle
Insulin resistance in pulmonary arterial hypertension
Eur. Respir. J.,
February 1, 2009;
33(2):
318 - 324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Brown Jr.
Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia
Schizophr Bull,
January 1, 2009;
35(1):
256 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Koenigsknecht-Talboo, M. Meyer-Luehmann, M. Parsadanian, M. Garcia-Alloza, M. B. Finn, B. T. Hyman, B. J. Bacskai, and D. M. Holtzman
Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-A{beta} Antibody Administration in PDAPP Mice
J. Neurosci.,
December 24, 2008;
28(52):
14156 - 14164.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Ji, J. Maeda, M. Sawada, M. Ono, T. Okauchi, M. Inaji, M.-R. Zhang, K. Suzuki, K. Ando, M. Staufenbiel, et al.
Imaging of Peripheral Benzodiazepine Receptor Expression as Biomarkers of Detrimental versus Beneficial Glial Responses in Mouse Models of Alzheimer's and Other CNS Pathologies
J. Neurosci.,
November 19, 2008;
28(47):
12255 - 12267.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Martens, J. Greenberg, and J. J. B. Allen
Self-Esteem and Autonomic Physiology: Parallels Between Self-Esteem and Cardiac Vagal Tone as Buffers of Threat
Personality and Social Psychology Review,
November 1, 2008;
12(4):
370 - 389.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. J. Yoon, S.-B. Jeon, I.-H. Kim, and E. J. Park
Regulation of TLR2 Expression by Prostaglandins in Brain Glia
J. Immunol.,
June 15, 2008;
180(12):
8400 - 8409.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Collino, N. S.A. Patel, and C. Thiemermann
Review: PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury
Therapeutic Advances in Cardiovascular Disease,
June 1, 2008;
2(3):
179 - 197.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. Wang and Y.-J. Y. Wan
Nuclear Receptors and Inflammatory Diseases
Experimental Biology and Medicine,
May 1, 2008;
233(5):
496 - 506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Kotilinek, M. A. Westerman, Q. Wang, K. Panizzon, G. P. Lim, A. Simonyi, S. Lesne, A. Falinska, L. H. Younkin, S. G. Younkin, et al.
Cyclooxygenase-2 inhibition improves amyloid-{beta}-mediated suppression of memory and synaptic plasticity
Brain,
March 1, 2008;
131(3):
651 - 664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Fang, W. Ye, K. Fall, M. Lekander, H. Wigzell, P. Sparen, H.-O. Adami, and U. Valdimarsdottir
Loss of a Child and the Risk of Amyotrophic Lateral Sclerosis
Am. J. Epidemiol.,
January 15, 2008;
167(2):
203 - 210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Luna-Medina, M. Cortes-Canteli, S. Sanchez-Galiano, J. A. Morales-Garcia, A. Martinez, A. Santos, and A. Perez-Castillo
NP031112, a Thiadiazolidinone Compound, Prevents Inflammation and Neurodegeneration under Excitotoxic Conditions: Potential Therapeutic Role in Brain Disorders
J. Neurosci.,
May 23, 2007;
27(21):
5766 - 5776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Hansmann, R. A. Wagner, S. Schellong, V. A. de Jesus Perez, T. Urashima, L. Wang, A. Y. Sheikh, R. S. Suen, D. J. Stewart, and M. Rabinovitch
Pulmonary Arterial Hypertension Is Linked to Insulin Resistance and Reversed by Peroxisome Proliferator-Activated Receptor-{gamma} Activation
Circulation,
March 13, 2007;
115(10):
1275 - 1284.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Franciosi, J. K. Ryu, H. B. Choi, L. Radov, S. U. Kim, and J. G. McLarnon
Broad-Spectrum Effects of 4-Aminopyridine to Modulate Amyloid beta1-42-Induced Cell Signaling and Functional Responses in Human Microglia.
J. Neurosci.,
November 8, 2006;
26(45):
11652 - 11664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Wilkinson, J. Koenigsknecht-Talboo, C. Grommes, C. Y. D. Lee, and G. Landreth
Fibrillar beta-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia
J. Biol. Chem.,
July 28, 2006;
281(30):
20842 - 20850.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R Bordet, P Gele, P Duriez, and J-C Fruchart
PPARs: a new target for neuroprotection.
J. Neurol. Neurosurg. Psychiatry,
March 1, 2006;
77(3):
285 - 287.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. L. Huang, P. P. Zandi, K. L. Tucker, A. L. Fitzpatrick, L. H. Kuller, L. P. Fried, G. L. Burke, and M. C. Carlson
Benefits of fatty fish on dementia risk are stronger for those without APOE {epsilon}4
Neurology,
November 8, 2005;
65(9):
1409 - 1414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. P. Townsend and D. Pratico
Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs
FASEB J,
October 1, 2005;
19(12):
1592 - 1601.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Koenigsknecht-Talboo and G. E. Landreth
Microglial Phagocytosis Induced by Fibrillar {beta}-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines
J. Neurosci.,
September 7, 2005;
25(36):
8240 - 8249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Schutz, J. Reimann, L. Dumitrescu-Ozimek, K. Kappes-Horn, G. E. Landreth, B. Schurmann, A. Zimmer, and M. T. Heneka
The Oral Antidiabetic Pioglitazone Protects from Neurodegeneration and Amyotrophic Lateral Sclerosis-Like Symptoms in Superoxide Dismutase-G93A Transgenic Mice
J. Neurosci.,
August 24, 2005;
25(34):
7805 - 7812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Luna-Medina, M. Cortes-Canteli, M. Alonso, A. Santos, A. Martinez, and A. Perez-Castillo
Regulation of Inflammatory Response in Neural Cells in Vitro by Thiadiazolidinones Derivatives through Peroxisome Proliferator-activated Receptor {gamma} Activation
J. Biol. Chem.,
June 3, 2005;
280(22):
21453 - 21462.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek, A. Hanke, I. Dewachter, C. Kuiperi, K. O'Banion, T. Klockgether, F. Van Leuven, and G. E. Landreth
Acute treatment with the PPAR{gamma} agonist pioglitazone and ibuprofen reduces glial inflammation and A{beta}1-42 levels in APPV717I transgenic mice
Brain,
June 1, 2005;
128(6):
1442 - 1453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-S. Shie, R. M. Breyer, and T. J. Montine
Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced A{beta} Phagocytosis yet Lack A{beta}-Activated Neurotoxicity
Am. J. Pathol.,
April 1, 2005;
166(4):
1163 - 1172.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Fuenzalida, M. C. Aguilera, D. G. Piderit, P. C. Ramos, D. Contador, V. Quinones, A. Rigotti, F. C. Bronfman, and M. Bronfman
Peroxisome Proliferator-activated Receptor {gamma} Is a Novel Target of the Nerve Growth Factor Signaling Pathway in PC12 Cells
J. Biol. Chem.,
March 11, 2005;
280(10):
9604 - 9609.
[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]
|
|
|
|
|
|
|
I. E. Camacho, L. Serneels, K. Spittaels, P. Merchiers, D. Dominguez, and B. De Strooper
Peroxisome Proliferator-Activated Receptor {gamma} Induces a Clearance Mechanism for the Amyloid-{beta} Peptide
J. Neurosci.,
December 1, 2004;
24(48):
10908 - 10917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Liao, D. Cheng, J. Wang, D. M. Duong, T. G. Losik, M. Gearing, H. D. Rees, J. J. Lah, A. I. Levey, and J. Peng
Proteomic Characterization of Postmortem Amyloid Plaques Isolated by Laser Capture Microdissection
J. Biol. Chem.,
August 27, 2004;
279(35):
37061 - 37068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Wang, M. J. Rowan, and R. Anwyl
{beta}-Amyloid-Mediated Inhibition of NMDA Receptor-Dependent Long-Term Potentiation Induction Involves Activation of Microglia and Stimulation of Inducible Nitric Oxide Synthase and Superoxide
J. Neurosci.,
July 7, 2004;
24(27):
6049 - 6056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Schmidt, E. Moric, M. Schmidt, M. Sastre, D. L. Feinstein, and M. T. Heneka
Anti-inflammatory and antiproliferative actions of PPAR-{gamma} agonists on T lymphocytes derived from MS patients
J. Leukoc. Biol.,
March 1, 2004;
75(3):
478 - 485.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Qin, Y. Liu, T. Wang, S.-J. Wei, M. L. Block, B. Wilson, B. Liu, and J.-S. Hong
NADPH Oxidase Mediates Lipopolysaccharide-induced Neurotoxicity and Proinflammatory Gene Expression in Activated Microglia
J. Biol. Chem.,
January 9, 2004;
279(2):
1415 - 1421.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zonta, A. Sebelin, S. Gobbo, T. Fellin, T. Pozzan, and G. Carmignoto
Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes
J. Physiol.,
December 1, 2003;
553(2):
407 - 414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sastre, I. Dewachter, G. E. Landreth, T. M. Willson, T. Klockgether, F. van Leuven, and M. T. Heneka
Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-{gamma} Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of {beta}-Secretase
J. Neurosci.,
October 29, 2003;
23(30):
9796 - 9804.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Sagi, S. Weggen, J. Eriksen, T. E. Golde, and E. H. Koo
The Non-cyclooxygenase Targets of Non-steroidal Anti-inflammatory Drugs, Lipoxygenases, Peroxisome Proliferator-activated Receptor, Inhibitor of {kappa}B Kinase, and NF{kappa}B, Do Not Reduce Amyloid {beta}42 Production
J. Biol. Chem.,
August 22, 2003;
278(34):
31825 - 31830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Yan, J. Zhang, H. Liu, S. Babu-Khan, R. Vassar, A. L. Biere, M. Citron, and G. Landreth
Anti-Inflammatory Drug Therapy Alters {beta}-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease
J. Neurosci.,
August 20, 2003;
23(20):
7504 - 7509.
[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]
|
|
|
|
|
|
|
E. J. Park, S. Y. Park, E.-h. Joe, and I. Jou
15d-PGJ2 and Rosiglitazone Suppress Janus Kinase-STAT Inflammatory Signaling through Induction of Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 in Glia
J. Biol. Chem.,
April 18, 2003;
278(17):
14747 - 14752.
[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]
|
|
|
|
|
|
|
N. G. Bazan and W. J. Lukiw
Cyclooxygenase-2 and Presenilin-1 Gene Expression Induced by Interleukin-1beta and Amyloid beta 42 Peptide Is Potentiated by Hypoxia in Primary Human Neural Cells
J. Biol. Chem.,
August 9, 2002;
277(33):
30359 - 30367.
[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]
|
|
|
|
|
|
|
L. Wang, H. Das, A. Kamath, L. Li, and J. F. Bukowski
Human V{gamma}2V{delta}2 T Cells Augment Migration-Inhibitory Factor Secretion and Counteract the Inhibitory Effect of Glucocorticoids on IL-1{beta} and TNF-{alpha} Production
J. Immunol.,
May 15, 2002;
168(10):
4889 - 4896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Clark
The role of PPARs in inflammation and immunity
J. Leukoc. Biol.,
March 1, 2002;
71(3):
388 - 400.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. A. Smits, A. J. van Beelen, N. M. de Vos, A. Rijsmus, T. van der Bruggen, J. Verhoef, F. L. van Muiswinkel, and H. S. L. M. Nottet
Activation of Human Macrophages by Amyloid-{{beta}} Is Attenuated by Astrocytes
J. Immunol.,
June 1, 2001;
166(11):
6869 - 6876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Combs, J. C. Karlo, S.-C. Kao, and G. E. Landreth
{beta}-Amyloid Stimulation of Microglia and Monocytes Results in TNF{alpha}-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis
J. Neurosci.,
February 15, 2001;
21(4):
1179 - 1188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. T. Heneka, T. Klockgether, and D. L. Feinstein
Peroxisome Proliferator-Activated Receptor-gamma Ligands Reduce Neuronal Inducible Nitric Oxide Synthase Expression and Cell Death In Vivo
J. Neurosci.,
September 15, 2000;
20(18):
6862 - 6867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. P. Lim, F. Yang, T. Chu, P. Chen, W. Beech, B. Teter, T. Tran, O. Ubeda, K. H. Ashe, S. A. Frautschy, et al.
Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease
J. Neurosci.,
August 1, 2000;
20(15):
5709 - 5714.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
