A basic amino acid in the cytoplasmic domain of Alzheimer's β-amyloid precursor protein (APP) is essential for cleavage of APP at the α-site

Abstract

In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) is thought to be produced as a result of the aberrant metabolism of β-amyloid precursor protein (APP). We report that the APP cytoplasmic domain contains a novel and important signal for APP metabolism. A single amino acid mutation that changed arginine at amino acid 747 of APP770 (corresponding to position 672 of APP695) to a non-basic amino acid greatly increased the production of intracellular APP carboxyl-terminal fragment(s) cleaved at β-site(s) (CTFβ), but did not result in increased secretion of Aβ40 and Aβ42. This was not due to a simple intracellular accumulation of CTFβ resulting from a lack of γ-secretase. CTFβ derived from this mutant APP was generated and degraded as efficiently as CTFβ derived from wild-type APP. This result indicates that the increase in the quantity of CTFβ does not always give rise to more Aβ production, as was previously suggested by studies of a familial AD mutation of APP. These findings suggest that APP carrying the substitution mutation at this basic amino acid may be metabolized by another protein secretory pathway. Although these results have not completely elucidated why CTFβ derived from the mutant APP escapes from subsequent cleavage by γ-secretase, analysis of the processing pathway of this mutant APP should provide insights into the pathogenesis of the sporadic type of AD.