title: Cellular prion protein expression is not regulated by the Alzheimer's amyloid precursor protein intracellular domain.
abstract: There is increasing evidence of molecular and cellular links between Alzheimer's disease (AD) and prion diseases. The cellular prion protein, PrP(C), modulates the post-translational processing of the AD amyloid precursor protein (APP), through its inhibition of the β-secretase BACE1, and oligomers of amyloid-β bind to PrP(C) which may mediate amyloid-β neurotoxicity. In addition, the APP intracellular domain (AICD), which acts as a transcriptional regulator, has been reported to control the expression of PrP(C). Through the use of transgenic mice, cell culture models and manipulation of APP expression and processing, this study aimed to clarify the role of AICD in regulating PrP(C). Over-expression of the three major isoforms of human APP (APP(695), APP(751) and APP(770)) in cultured neuronal and non-neuronal cells had no effect on the level of endogenous PrP(C). Furthermore, analysis of brain tissue from transgenic mice over-expressing either wild type or familial AD associated mutant human APP revealed unaltered PrP(C) levels. Knockdown of endogenous APP expression in cells by siRNA or inhibition of γ-secretase activity also had no effect on PrP(C) levels. Overall, we did not detect any significant difference in the expression of PrP(C) in any of the cell or animal-based paradigms considered, indicating that the control of cellular PrP(C) levels by AICD is not as straightforward as previously suggested.
authors.affiliation: Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lewis
authors.forename: Isobel J
authors.initials: IJ
authors.lastname: Whitehouse
authors.forename: Herbert
authors.initials: H
authors.lastname: Baybutt
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Hooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D050505:Mutant Proteins; D011328:Prions; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases