Regulation of β-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor α

Combs, Colin K.; Bates, Patricia; Karlo, J. Colleen; Landreth, Gary E.

doi:10.1016/s0197-0186(01)00052-3

Cited by 94 publications

(67 citation statements)

References 47 publications

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“…We have shown previously that exposure of primary microglia and THP-1 monocytes to fibrillar ␤-amyloid peptides resulted in the production and secretion of various proinflammatory cytokines, including IL-1␣, IL-1␤, IL-6, and tumor necrosis factor ␣ (TNF␣), and the production of reactive oxygen species (ROS) and nitrogen species (McDonald et al, 1997;Combs et al, 1999Combs et al, , 2000Combs et al, , 2001aBamberger et al, 2003). These studies have demonstrated that microglia and monocytes interact and respond to fibrillar forms of A␤ 1-40 , A␤ 1-42 , or A␤ 25-35 with similar efficiency.…”

Section: Statins Inhibit the Production Of Il-1␤ After A␤ Exposurementioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Cordle¹,

Landreth²

2005

J. Neurosci.

161

109

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Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar ␤-amyloid (A␤) in the brain, a fulminant microglialmediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the A␤-stimulated expression of interleukin-1␤ and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal A␤ production and microglia-directed inflammation.

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Section: Statins Inhibit the Production Of Il-1␤ After A␤ Exposurementioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Cordle¹,

Landreth²

2005

J. Neurosci.

161

109

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“…Mice were immunized with 200 l of pMOG 35-55 /CFA emulsion s.c. at the base of the tail. For the EAE studies, mice were simultaneously injected with 50 l of pertussis toxin (200 ng) i.p.…”

Section: Feeding Immunization and Assessment Of Eaementioning

confidence: 99%

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Cunard

DiCampli

Archer

et al. 2002

The Journal of Immunology

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARα and PPARγ are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARα ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARα ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35–55 (pMOG35–55), following immunization with pMOG35–55/CFA. Following in vitro restimulation with pMOG35–55, splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-γ, IL-6, and TNF-α despite similar proliferative responses. We also demonstrate higher expression of PPARα in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARα-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

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“…Equal amounts of protein (20 g) in Laemmli buffer were first boiled for 7 min, then run on SDS-PAGE gels. Gels were then transferred onto polyvinylidene difluoride membranes as described previously (Combs et al, 2001). The blots were then incubated in monoclonal 4G10 antibody (1:1000; Upstate Biotechnology, Lake Placid, NY) or rabbit anti-Erk1/2 (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Introductionmentioning

confidence: 99%

Effects of Alzheimer's Disease on Different Cortical Layers: The Role of Intrinsic Differences in Aβ Susceptibility

Romito-DiGiacomo¹,

Menegay²,

Cicero³

et al. 2007

J. Neurosci.

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Alzheimer's disease is late life dementia associated with significant neurodegeneration in both cortical and subcortical regions. During the ϳ10 year course of the disease, neurons are lost in a progressive pattern that is relatively consistent among individuals. One example of this is the progression of disease pathology found in both the neocortex and archicortex. In these structures, the earliest problems can be found in superficial cortical layers (II-IV), whereas later the disease advances to involve the deeper cortical layers (V-VI). It is unclear whether these apparent differences in sensitivity are intrinsic to the neurons or imposed by external factors such as the pattern of connections. We used ␤-amyloid (A␤) peptide treatment of cultured mouse neurons as our model system. We show first that, as in hippocampus, dissociated cultures of embryonic cortical neurons are biased toward the survival of cells that were finishing division in the ventricular zone at the time of harvest. Thus, embryonic day 13.5 (E13.5) cultures contain primarily deep-layer neurons whereas E16.5 cultures contain cells destined for upper layers. We use this cell-type specific segregation to our advantage and show, using both differences in gene expression profiles and A␤ survival curves, that deeper layer neurons are significantly more resistant to the toxic effects of A␤ than are cells from the more superficial strata. This suggests that an intrinsic underlying biology drives at least part of the AD progression pattern and that the time of harvest is a crucial variable in the interpretation of any cortical culture experiment.

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Regulation of β-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor α

Cited by 94 publications

References 47 publications

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

WY14,643, a PPARα Ligand, Has Profound Effects on Immune Responses In Vivo

Effects of Alzheimer's Disease on Different Cortical Layers: The Role of Intrinsic Differences in Aβ Susceptibility

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