Abstract

INSILCO MODE OF ANALYSIS TO PREDICT THE ROLE OF COPPER IONS IN THE ALZHEIMER'S

S.M.A. Shahid*, M.A. Khalid, Muhannad Saud A. Alshammari, Muteb Nasser Hamad Alawad and Mohammed Saqer Fhaid Alshammari

ABSTRACT

Amyloid precursor protein (APP) can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. One of the consequences of Cu(II) binding to APP is thought to be neuronal toxicity which has been demonstrated so far in cultured neurones. The hypothesised role of CuBD in neuronal toxicity is that the bound Cu(II) is reduced to Cu(I), which can then lead to lipoprotein peroxidation and free radicals that damage the cell (White et al. 2002). Cu(II)- bound CuBD of human APP appears suficient in the generation of Cu(I) and causing neuronal cell death (White et al. 2002). We describe here the structure of Cu(2+)-bound CuBD reveals that the metal ligands are His147, His151, Tyr168 and two water molecules, which are arranged in a square pyramidal geometry. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease.

Keywords: Alzheimer’s disease, APP, CuBD, metalloprotein, Amyloid-beta (A?) peptide.