Biochemistry and Pharmacology - Research Publications

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Author: Cappai, Roberto × Type: Journal Article × Start date: 2008 × End date: 2009 ×

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    An update on the toxicity of Abeta in Alzheimer's disease.
    Götz, J ; Ittner, LM ; Schonrock, N ; Cappai, R (Informa UK Limited, 2008-12)
    Alzheimer's disease is characterized histopathologically by deposition of insoluble forms of the peptide Abeta and the protein tau in brain. Abeta is the principal component of amyloid plaques and tau of neurofibrillary tangles. Familial cases of AD are associated with causal mutations in the gene encoding the amyloid precursor protein, APP, from which the amyloidogenic Abeta peptide is derived, and this supports a role for Abeta in disease. Abeta can promote tau pathology and at the same time its toxicity is also tau-dependent. Abeta can adopt different conformations including soluble oligomers and insoluble fibrillar species present in plaques. We discuss which of these conformations exert toxicity, highlight molecular pathways involved and discuss what has been learned by applying functional genomics.
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    Copper binding to the Alzheimer's disease amyloid precursor protein
    Kong, GK-W ; Miles, LA ; Crespi, GAN ; Morton, CJ ; Ng, HL ; Barnham, KJ ; McKinstry, WJ ; Cappai, R ; Parker, MW (SPRINGER, 2008-03)
    Alzheimer's disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called A beta by proteolysis of the 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 A beta 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. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. 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 A beta production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer's disease.