Abstract
The amyloidogenic pathway leading to the production and deposition of Abeta peptides, major constituents of Alzheimer disease senile plaques, is linked to neuronal metal homeostasis. The amyloid precursor protein binds copper and zinc in its extracellular domain, and the Abeta peptides also bind copper, zinc, and iron. The first step in the generation of Abeta is cleavage of amyloid precursor protein by the aspartic protease BACE1. Here we show that BACE1 interacts with CCS (the copper chaperone for superoxide dismutase-1 (SOD1)) through domain I and the proteins co-immunoprecipitate from rat brain extracts. We have also been able to visualize the co-transport of membranous BACE1 and soluble CCS through axons. BACE1 expression reduces the activity of SOD1 in cells consistent with direct competition for available CCS as overexpression of CCS restores SOD1 activity. Finally, we demonstrate that the twenty-four residue C-terminal domain of BACE1 binds a single Cu(I) atom with high affinity through cysteine residues.
Highlights
A major pathological hallmark of Alzheimer disease is the presence of senile plaques in the brain
1 The abbreviations used are: APP, amyloid precursor protein; SOD1, superoxide dismutase-1; GST, glutathione S-transferase; BCS, bathocuproine disulfonic acid; GFP, green fluorescent protein; CHO, Chinese hamster ovary; CCS, copper chaperone for SOD1
The Cytoplasmic Domain of BACE1 Interacts with Domain I of Human CCS—We carried out a yeast two-hybrid screen using the cytoplasmic domain of BACE1 as “bait” and identified an interaction with CCS, the copper chaperone for SOD1
Summary
A major pathological hallmark of Alzheimer disease is the presence of senile plaques in the brain. In a screen for peptides that may interact with the short cytosolic domain of BACE1, we recovered CCS, the copper delivery protein for copper/zinc superoxide dismutase, SOD1 [5]. We establish that it is the N-terminal copper-binding domain of CCS that interacts with BACE1. We have found that overexpression of BACE1 does reduce SOD1 activity in cells consistent with our hypothesis, and increasing levels of CCS restore SOD1 activity in these cells. Alterations in copper metabolism are strongly linked to Alzheimer disease, both APP and A bind copper, and copper is present within amyloid plaques [11,12,13,14,15,16]. Senile plaques are enriched in metals, copper and zinc, and modulating copper availability can influence amyloid pathology in animal models of Alzheimer disease [21, 22].
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