Linked Life Data

18421302

Source:http://linkedlifedata.com/resource/pubmed/id/18421302

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2008-8-19
pubmed:abstractText
According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by beta-amyloid (Abeta), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated gamma-secretase activity and Abeta generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates gamma-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of gamma-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced gamma-secretase activity. Moreover, glutathione depletion significantly facilitated gamma-secretase activity and Abeta generation by enhancing the formation of higher molecular weight gamma-secretase complex before signs of cell death developed. Finally, Abeta treatment, a known inducer of oxidative stress, also increased gamma-secretase activity. Taken together, these results indicate that DDIA-induced gamma-secretase activation is dependent on augmented oxidative stress, and that Abeta and gamma-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Abeta generation mediated by gamma-secretase activation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1350-9047
pubmed:author
pubmed:issnType
Print
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1375-84
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:18421302-Amyloid Precursor Protein Secretases, pubmed-meshheading:18421302-Amyloid beta-Peptides, pubmed-meshheading:18421302-Animals, pubmed-meshheading:18421302-Apoptosis, pubmed-meshheading:18421302-CHO Cells, pubmed-meshheading:18421302-Camptothecin, pubmed-meshheading:18421302-Cricetinae, pubmed-meshheading:18421302-Cricetulus, pubmed-meshheading:18421302-Cytochromes c, pubmed-meshheading:18421302-DNA Damage, pubmed-meshheading:18421302-Enzyme Activation, pubmed-meshheading:18421302-Etoposide, pubmed-meshheading:18421302-Glutathione, pubmed-meshheading:18421302-Humans, pubmed-meshheading:18421302-Mice, pubmed-meshheading:18421302-Mitochondria, pubmed-meshheading:18421302-Mitochondrial Membrane Transport Proteins, pubmed-meshheading:18421302-Oxidative Stress, pubmed-meshheading:18421302-Reactive Oxygen Species
pubmed:year
2008
pubmed:articleTitle
DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress.
pubmed:affiliation
Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't