Journal Article Alternative Selection of beta-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid beta-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the A beta Sequence

Kimura, Ayano  ,  Hata, Saori  ,  Suzuki, Toshiharu

291 ( 46 )  , pp.24041 - 24053 , 2016-11-11 , American Society for Biochemistry and Molecular Biology (ASBMB)
beta-Site APP-cleaving enzyme 1 (BACE1) cleaves amyloid -protein precursor (APP) at the bond between Met(671) and Asp(672) (-site) to generate the carboxyl-terminal fragment (CTF/C99). BACE1 also cleaves APP at another bond between Thr(681) and Gln(682) (-site), yielding CTF/C89. Cleavage of CTF/C99 by -secretase generates A(1-XX), whereas cleavage of CTF/C89 generates A(11-XX). Thus, -site cleavage by BACE1 is amyloidolytic rather than amyloidogenic. cleavage of mouse APP is more common than the corresponding cleavage of human APP. We found that the H684R substitution within human A, which replaces the histidine in the human protein with the arginine found at the corresponding position in mouse, facilitated cleavage irrespective of the species origin of BACE1, thereby significantly increasing the level of A(11-XX) and decreasing the level of A(1-XX). Thus, amino acid substitutions within the A sequence influenced the selectivity of alternative - or -site cleavage of APP by BACE1. In familial Alzheimer's disease (FAD), the APP gene harbors pathogenic variations such as the Swedish (K670N/M671L), Leuven (E682K), and A673V mutations, all of which decrease A(11-40) generation, whereas the protective Icelandic mutation (A673T) increases generation of A(11-40). Thus, A673T promotes cleavage of APP and protects subjects against AD. In addition, CTF/C99 was cleaved by excess BACE1 activity to generate CTF/C89, followed by A(11-40), even if APP harbored pathogenic mutations. The resultant A(11-40) was more metabolically labile in vivo than A(1-40). Our analysis suggests that some FAD mutations in APP are amyloidogenic and/or amyloidolytic via selection of alternative BACE1 cleavage sites.

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