Prion Protein Interacts with BACE1 Protein and Differentially Regulates Its Activity toward Wild Type and Swedish Mutant Amyloid Precursor Protein

Abstract

In Alzheimer disease amyloid-␤ (A␤) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the ␤-secretase BACE1 is the rate-limiting step in the production of A␤. We have reported previously that the cellular prion protein (PrP C ) inhibited the action of BACE1 toward human wild type APP (APP WT ) in cellular models and that the levels of endogenous murine A␤ were significantly increased in PrP C -null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation.

Cellular prion protein modulates β-amyloid deposition in aged APP/PS1 transgenic mice

“…We observed no variation in BACE1 expression in older animals, thereby ruling out this possibility. In fact some report indicated that the deletion of PrP c did not affected APP or Aß deposition in AD mouse model (Griffiths et al, 2011) .Moreover, our in vivo results revealed a significant increase in Ab deposits in older animals expressing high PrP c levels, with no significant effect on APP or BACE1 levels. Based on these findings, it is tempting to speculate that it is not basal amyloid levels that are modified but, rather, secondary events associated with the degradation or alternative production of amyloid.…”

The P’s and Q’s of cellular PrP-Aβ interactions

“…40 These workers have gone further to define an antiamyloidogenic effect arising from an interaction with the protease prodomain impeding BACE maturation. 41 …”

The effects of the cellular and infectious prion protein on the neuronal adaptor protein X11α

“…X11α has been linked with numerous regulation pathways within the cell, including but not limited to controlling amyloidogenic processing of APP [7], and regulation of the antioxidant copper/zinc superoxide dismutase, SOD1 [8]. As PrP C has been shown to play a role in the regulation of Aβ peptide production [3] and PrP Sc has been shown to influence SOD1 levels [1], this work investigated a potential role for PrP C in controlling X11α.…”

“…PrP C itself has been linked with regulating cellular mechanisms, including oxidative stress and metal metabolism [1] and more recently with disease progression in Alzheimer's disease (AD) [2][3][4]. AD etiology is linked with the build-up of amyloid beta (Aβ) peptides, which are produced during the amyloidogenic processing of the amyloid precursor protein (APP) [2].…”