Linked Life Data

1346802

Source:http://linkedlifedata.com/resource/pubmed/id/1346802

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
1992-3-20
pubmed:abstractText
In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0270-6474
pubmed:author
pubmed:issnType
Print
pubmed:volume
12
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
376-89
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:1346802-Amino Acid Sequence, pubmed-meshheading:1346802-Amyloid beta-Peptides, pubmed-meshheading:1346802-Calcimycin, pubmed-meshheading:1346802-Calcium, pubmed-meshheading:1346802-Cell Survival, pubmed-meshheading:1346802-Cells, Cultured, pubmed-meshheading:1346802-Cerebral Cortex, pubmed-meshheading:1346802-Dose-Response Relationship, Drug, pubmed-meshheading:1346802-Fetus, pubmed-meshheading:1346802-Glutamates, pubmed-meshheading:1346802-Glutamic Acid, pubmed-meshheading:1346802-Homeostasis, pubmed-meshheading:1346802-Humans, pubmed-meshheading:1346802-Indicators and Reagents, pubmed-meshheading:1346802-Kinetics, pubmed-meshheading:1346802-Molecular Sequence Data, pubmed-meshheading:1346802-Nerve Degeneration, pubmed-meshheading:1346802-Neurons, pubmed-meshheading:1346802-Peptide Fragments, pubmed-meshheading:1346802-Structure-Activity Relationship
pubmed:year
1992
pubmed:articleTitle
beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity.
pubmed:affiliation
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't