Linked Life Data

18987181

Source:http://linkedlifedata.com/resource/pubmed/id/18987181

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2008-11-6
pubmed:abstractText
Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1529-2401
pubmed:author
pubmed:issnType
Electronic
pubmed:day
5
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
11445-53
pubmed:meshHeading
pubmed-meshheading:18987181-Analysis of Variance, pubmed-meshheading:18987181-Animals, pubmed-meshheading:18987181-Animals, Newborn, pubmed-meshheading:18987181-Apolipoproteins E, pubmed-meshheading:18987181-Brain, pubmed-meshheading:18987181-Cells, Cultured, pubmed-meshheading:18987181-Culture Media, Conditioned, pubmed-meshheading:18987181-DNA Mutational Analysis, pubmed-meshheading:18987181-Dose-Response Relationship, Drug, pubmed-meshheading:18987181-Humans, pubmed-meshheading:18987181-Hydrocarbons, Fluorinated, pubmed-meshheading:18987181-Male, pubmed-meshheading:18987181-Mice, pubmed-meshheading:18987181-Mice, Transgenic, pubmed-meshheading:18987181-Neuroglia, pubmed-meshheading:18987181-Polymorphism, Genetic, pubmed-meshheading:18987181-RNA, Messenger, pubmed-meshheading:18987181-Sulfonamides, pubmed-meshheading:18987181-Time Factors
pubmed:year
2008
pubmed:articleTitle
Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
pubmed:affiliation
Discovery Neuroscience, Wyeth Research, CN8000, Princeton, New Jersey 08543, USA. riddeld@wyeth.com
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't