Linked Life Data

15758166

Source:http://linkedlifedata.com/resource/pubmed/id/15758166

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2005-3-10
pubmed:abstractText
Although abundant reactive microglia are found associated with beta-amyloid (Abeta) plaques in Alzheimer's disease (AD) brains, their contribution to cell loss remains speculative. A variety of studies have documented the ability of Abeta fibrils to directly stimulate microglia in vitro to assume a neurotoxic phenotype characterized by secretion of a plethora of proinflammatory molecules. Collectively, these data suggest that activated microglia play a direct role in contributing to neuron death in AD rather than simply a role in clearance after plaque deposition. Although it is clear the Abeta-stimulated microglia acutely secrete toxic oxidizing species, the identity of longer-lived neurotoxic agents remains less defined. We used Abeta-stimulated conditioned media from primary mouse microglia to identify more stable neurotoxic secretions. The NMDA receptor antagonists memantine and 2-amino-5-phosphopetanoic acid as well as soluble tumor necrosis factor alpha (TNFalpha) receptor protect neurons from microglial-conditioned media-dependent death, implicating the excitatory neurotransmitter glutamate and the proinflammatory cytokine TNFalpha as effectors of microglial-stimulated death. Neuron death occurs in an oxidative damage-dependent manner, requiring activity of inducible nitric oxide synthase. Toxicity results from coincident stimulation of the TNFalpha and NMDA receptors, because stimulations of either alone are insufficient to initiate cell death. These findings suggest the hypothesis that AD brains provide the appropriate microglial-mediated inflammatory environment for TNFalpha and glutamate to synergistically stimulate toxic activation of their respective signaling pathways in neurons as a contributing mechanism of cell death.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
25
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2566-75
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:15758166-Amyloid beta-Peptides, pubmed-meshheading:15758166-Animals, pubmed-meshheading:15758166-Cell Death, pubmed-meshheading:15758166-Cells, Cultured, pubmed-meshheading:15758166-Cerebral Cortex, pubmed-meshheading:15758166-Culture Media, Conditioned, pubmed-meshheading:15758166-Dose-Response Relationship, Drug, pubmed-meshheading:15758166-Drug Synergism, pubmed-meshheading:15758166-Female, pubmed-meshheading:15758166-Glutamic Acid, pubmed-meshheading:15758166-Humans, pubmed-meshheading:15758166-Mice, pubmed-meshheading:15758166-Mice, Inbred C57BL, pubmed-meshheading:15758166-Microglia, pubmed-meshheading:15758166-Neurons, pubmed-meshheading:15758166-Pregnancy, pubmed-meshheading:15758166-Receptors, N-Methyl-D-Aspartate, pubmed-meshheading:15758166-Tumor Necrosis Factor-alpha
pubmed:year
2005
pubmed:articleTitle
Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors.
pubmed:affiliation
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural