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

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