Linked Life Data

12792666

Source:http://linkedlifedata.com/resource/pubmed/id/12792666

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2003-6-6
pubmed:abstractText
Genetic and neuropathological studies suggest that processing of amyloid precursor protein (APP) to yield amyloid beta-protein (Abeta) plays an important role in the pathogenesis of Alzheimer's disease (AD). One of the current therapeutic efforts for AD is directed towards blocking the gamma-secretase activity that produces Abeta. Compelling evidence for presenilin (PS) possessing gamma-secretase activity includes a lack of Abeta production in PS knockout neurons and in cultured cells carrying a dominant negative mutation at either of two critical aspartate residues in PS, which may constitute the active site of gamma-secretase. In vitro studies have shown a binding of transition-state analog gamma-secretase inhibitors to PS N-terminal fragment (NTF) and C-terminal fragment (CTF), the functional form of PS detected in the high-molecular-weight gamma-secretase complex that also contains nicastrin, Aph-1 and PEN-2. Conversion of full-length PS into functional NTF and CTF is mediated by an unknown protease activity named presenilinase. Endoproteolysis of PS into NTF/CTF by presenilinase also requires two critical aspartate residues, suggesting that full-length PS may undergo autoproteolysis and PS itself is presenilinase. Similar to gamma-secretase, presenilinase seems to be an aspartyl protease, as aspartyl protease inhibitor pepstatin A is the most potent inhibitor toward presenilinase among different classes of protease inhibitors. While several well-characterized gamma-secretase inhibitors can block presenilinase activity in vivo and in vitro, the potency of inhibitors blocking presenilinase and gamma-secretase are not correlated. Lack of presenilinase inhibition by several potent gamma-secretase inhibitors suggests that these two protease activities are pharmacologically distinct.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases, http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides, http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/BACE1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases, http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins, http://linkedlifedata.com/resource/pubmed/chemical/PSEN1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/PSEN2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Presenilin-1, http://linkedlifedata.com/resource/pubmed/chemical/Presenilin-2, http://linkedlifedata.com/resource/pubmed/chemical/presenilinase, human
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0214-0934
pubmed:author
pubmed:copyrightInfo
(c) 2003 Prous Science. All rights reserved.
pubmed:issnType
Print
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
69-74
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Relationship between presenilinase and gamma-secretase.
pubmed:affiliation
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Harvard Institutes for Medicine, Boston, Massachusetts 02115, USA. wxia@rics.bwh.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Review