Cellular Prion Protein Expression Is Not Regulated by the Alzheimer's Amyloid Precursor Protein Intracellular Domain

Victoria Lewis,Nigel M Hooper,Isobel J Whitehouse,Jean C Manson,Herbert Baybutt,Steven J Collins

doi:10.1371/journal.pone.0031754

Abstract

There is increasing evidence of molecular and cellular links between Alzheimer's disease (AD) and prion diseases. The cellular prion protein, PrPC, 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 PrPC 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 PrPC. 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 PrPC. Over-expression of the three major isoforms of human APP (APP695, APP751 and APP770) in cultured neuronal and non-neuronal cells had no effect on the level of endogenous PrPC. Furthermore, analysis of brain tissue from transgenic mice over-expressing either wild type or familial AD associated mutant human APP revealed unaltered PrPC levels. Knockdown of endogenous APP expression in cells by siRNA or inhibition of γ-secretase activity also had no effect on PrPC levels. Overall, we did not detect any significant difference in the expression of PrPC in any of the cell or animal-based paradigms considered, indicating that the control of cellular PrPC levels by AICD is not as straightforward as previously suggested.

Highlights

Alzheimer’s disease (AD) and prion diseases fall within the spectrum of neurodegenerative diseases which are causally linked to misfolded and aggregated proteins
We looked to advance this research by determining whether the control of PrPC expression by APP intracellular domain (AICD) was specific to a particular amyloid precursor protein (APP) isoform
In contrast to previously published results [22], there was a significant 2–3-fold increase in APP in the cells transfected with any of the three APP isoforms, there was no significant difference in PrPC level in any of the APP isoform expressing cells when compared to the Hyg vector-only controls

Summary

Introduction

Alzheimer’s disease (AD) and prion diseases fall within the spectrum of neurodegenerative diseases which are causally linked to misfolded and aggregated proteins. Recent studies have shown more direct molecular links between AD and prion diseases, and the proteins at the centre of these diseases; namely the amyloid precursor protein (APP) and its proteolytic cleavage product the amyloid-b (Ab) peptide which deposits as plaques in the AD brain, and the normal cellular prion protein (PrPC) and the disease-associated isoform PrPSc, which accumulates in prion diseases. A substantive molecular link was provided when PrPC was shown to modulate production of Ab from wild type APP, through an interaction with the b-secretase BACE1 [5], later demonstrated to be a mechanism for altered trafficking and localisation of BACE1 resulting in reduced Ab production [6]. Whilst perhaps explained by methodological differences, these opposing results underscore the complexity in the possible interactions between these two key proteins and diseases

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