Gene knockout of amyloid precursor protein and amyloid precursor‐like protein‐2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts

Abstract

Alzheimer's disease is characterised by the accumulation of amyloid‐β peptide, which is cleaved from the copper‐binding amyloid‐β precursor protein. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for amyloid‐β precursor protein and amyloid‐β in copper homeostasis. Amyloid‐β precursor protein is a member of a multigene family, including amyloid precursor‐like proteins‐1 and ‐2. The copper‐binding domain is similar among amyloid‐β precursor protein family members, suggesting an overall conservation in its function or activity. Here, we demonstrate that double knockout of amyloid‐β precursor protein and amyloid precursor‐like protein‐2 expression results in significant increases in copper accumulation in mouse primary cortical neurons and embryonic fibroblasts. In contrast, over‐expression of amyloid‐β precursor protein in transgenic mice results in significantly reduced copper levels in primary cortical neurons. These findings provide cellular neuronal evidence for the role of amyloid‐β precursor protein in copper homeostasis and support the existing hypothesis that amyloid‐β precursor protein and amyloid precursor‐like protein‐2 are copper‐binding proteins with functionally interchangeable roles in copper homeostasis.