Cellular prion protein expression is not regulated by the Alzheimer's amyloid precursor protein intracellular domain

• Published in: PloS one 2012-02, Vol.7 (2), p.e31754
• Main Authors: Lewis, Victoria, Whitehouse, Isobel J, Baybutt, Herbert, Manson, Jean C, Collins, Steven J, Hooper, Nigel M
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amyloid beta-protein; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animal models; Animals; b-Site APP cleaving enzyme 1; Biology; Brain; Cell culture; Cell Line; Cellular biology; Creutzfeldt-Jakob disease; Gene Knockdown Techniques; Gene Silencing; Genetic engineering; Humans; Inhibition; Intracellular; Isoforms; Medicine; Mice; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutation; Neuroblastoma; Neurodegenerative diseases; Neurons; Neurotoxicity; Oligomers; Overexpression; Post-translation; Precursors; Prion protein; Prions (Proteins); Prions - metabolism; Protein expression; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Tertiary; Proteins; Secretase; siRNA; Structure-Activity Relationship; Transcription; Transgenic mice; β-Site APP-cleaving enzyme 1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031754

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.