Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and Swedish mutant amyloid precursor protein

In Alzheimer disease amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP) accumulate in the brain. Cleavage of APP by the β-secretase BACE1 is the rate-limiting step in the production of Aβ. 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 Aβ were significantly increased in PrP C-null mouse brain. Here we investigated the molecular and cellular mechanisms underlying this observation. PrP C interacted directly with the prodomain of the immature Golgi-localized form of BACE1. This interaction decreased BACE1 at the cell surface and in endosomes where it preferentially cleaves APP WT but increased it in the Golgi where it preferentially cleaves APP with the Swedish mutation (APP Swe). In transgenic mice expressing human APP with the Swedish and Indiana familial mutations (APP Swe,Ind), PrP C deletion had no influence on APP proteolytic processing, Aβ plaque deposition, or levels of soluble Aβ or Aβ oligomers. In cells, although PrP C inhibited the action of BACE1 on APP WT, it did not inhibit BACE1 activity toward APP Swe. The differential subcellular location of the BACE1 cleavage of APP Swe relative to APP WT provides an explanation for the failure of PrP C deletion to affect Aβ accumulation in APP Swe,Ind mice. Thus, although PrP C exerts no control on cleavage of APP Swe by BACE1, it has a profound influence on the cleavage of APP WT, suggesting that PrP C may be a key protective player against sporadic Alzheimer disease.