The Histidine Composition of the Amyloid-β Domain, but not the E1 Copper Binding Domain, Modulates β-Secretase Processing of Amyloid-β Protein Precursor in Alzheimer's Disease

Article type: Short Communication

Authors: Gough, Mallory | Blanthorn-Hazell, Sophee | Parkin, Edward T.^{; *}

Affiliations: Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK

Correspondence: [*] Correspondence to: Edward T. Parkin, Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK. Tel.: +44 1524592246; Fax: +44 1524 593192; E-mail: e.parkin@lancaster.ac.uk.

Abstract: Amyloid-β protein precursor (AβPP) proteolysis by β- and γ-secretases generates neurotoxic amyloid-β (Aβ)-peptides in Alzheimer's disease (AD). We have investigated the role of histidine residues within the extracellular E1 copper binding and Aβ domains of AβPP in its proteolysis. By stably expressing histidine to alanine AβPP mutant constructs in SH-SY5Y cells, we show that mutations in the E1 copper binding domain had no impact on α- or β-secretase processing. Mutation of histidine 14 within the Aβ-domain specifically down-regulated β-secretase processing without impacting on non-amyloidogenic proteolysis. Understanding how histidine 14 participates in AβPP proteolysis may reveal new intervention points for AD treatments.

Keywords: Amyloid-β protein precursor, amyloidogenic processing, β-secretase, histidine 14

DOI: 10.3233/JAD-141650

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1163-1168, 2015