title: LDLR expression and localization are altered in mouse and human cell culture models of Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism.
  
  
  RESULTS
  Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.
  
  
  CONCLUSIONS
  These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.
authors.affiliation: Byrd Alzheimer's Institute, Tampa, Florida, United States of America.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Abisambra
authors.forename: Tina
authors.initials: T
authors.lastname: Fiorelli
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
authors.forename: Peter
authors.initials: P
authors.lastname: Neame
authors.forename: Inge
authors.initials: I
authors.lastname: Wefes
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014404:Tubulin / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011973:Receptors, LDL; D014404:Tubulin