Prion protein interacts with bace1 and differentially regulates its activity towards 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

The CLIMPACTS synthesis report: An assessment of the effects of climate change and variation in New Zealand using the CLIMPACTS system

In the late 1980s, New Zealand undertook the first national assessment of climate change and its possible impacts on the country.The landmark report, reflecting the judgement of scores of national experts, called for greater efforts in building the national research capacity in order to better quantify the range of impacts that could occur in New Zealand from climate change and variability. In response, the collaborative CLIMPACTS Programme was established to provide this capacity. Ten years on from the first national assessment, the present synthesis offers some results from, as well as a demonstration of, the capacity developed by the CLIMPACTS Programme. The purpose of the present document is to provide a summary report from the CLIMPACTS Programme on climate change and its effects on New Zealand.The chapters and their contents are not comprehensive. Rather, they are focused on a specific set of questions, which conform to the particular expertise of the CLIMPACTS Programme members and which employ a limited set of the wide range of tools available within the CLIMPACTS Model. Other important areas such as forests, indigenous ecosystems and pests and diseases are not yet covered

State of the Climate in 2012

International audienceEditors note: For easy download the posted pdf of the State of the Climate for 2012 is a very low-resolution file. A high-resolution copy of the report is available by clicking here. Please be patient as it may take a few minutes for the high-resolution file to download