Linked Life Data

16597739

Source:http://linkedlifedata.com/resource/pubmed/id/16597739

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2006-4-6
pubmed:abstractText
gamma-Secretase processing of the amyloid precursor protein (APP) generates Abeta40 and Abeta42, peptides that constitute the principal components of the beta-amyloid plaque pathology of Alzheimer's disease (AD). The gamma-secretase activity is executed by a high-molecular-weight complex of which presenilin 1 (PS1) is an essential component. PS1 is a multi-pass membrane protein, and the large hydrophilic loop domain between transmembrane domains 6 and 7 has been shown to interact with various proteins. To determine the physiological function of the loop domain, we created a strain of PS1 knock-in mice in which the exon 10, which encodes most of the hydrophilic loop sequence, was deleted from the endogenous PS1 gene. We report here that the homozygous exon 10-deleted mice are viable but exhibit drastically reduced gamma-secretase cleavage at the Abeta40, but not the Abeta42, site. Surprisingly, this reduction of Abeta40 is associated with exacerbated plaque pathology when expressed on APP transgenic background. Thus, the PS1 loop plays a regulatory role in gamma-secretase processing, and decreased Abeta40, not increased Abeta42 is likely the cause for the accelerated plaque deposition in these animals. Our finding supports a protective role of Abeta40 against amyloid pathology and raises the possibility that impaired gamma-secretase activity could be the basis for AD pathogenesis in general.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
5
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3845-54
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology.
pubmed:affiliation
Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural