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Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence.
J Biol Chem. 2016 Nov 11; 291(46):24041-24053.JB

Abstract

β-Site APP-cleaving enzyme 1 (BACE1) cleaves amyloid β-protein precursor (APP) at the bond between Met671 and Asp672 (β-site) to generate the carboxyl-terminal fragment (CTFβ/C99). BACE1 also cleaves APP at another bond between Thr681 and Gln682 (β'-site), yielding CTFβ'/C89. Cleavage of CTFβ/C99 by γ-secretase generates Aβ(1-XX), whereas cleavage of CTFβ'/C89 generates Aβ(11-XX). Thus, β'-site cleavage by BACE1 is amyloidolytic rather than amyloidogenic. β' cleavage of mouse APP is more common than the corresponding cleavage of human APP. We found that the H684R substitution within human Aβ, which replaces the histidine in the human protein with the arginine found at the corresponding position in mouse, facilitated β' cleavage irrespective of the species origin of BACE1, thereby significantly increasing the level of Aβ(11-XX) and decreasing the level of Aβ(1-XX). Thus, amino acid substitutions within the Aβ sequence influenced the selectivity of alternative β- or β'-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 Aβ(11-40) generation, whereas the protective Icelandic mutation (A673T) increases generation of Aβ(11-40). Thus, A673T promotes β' cleavage of APP and protects subjects against AD. In addition, CTFβ/C99 was cleaved by excess BACE1 activity to generate CTFβ'/C89, followed by Aβ(11-40), even if APP harbored pathogenic mutations. The resultant Aβ(11-40) was more metabolically labile in vivo than Aβ(1-40). Our analysis suggests that some FAD mutations in APP are amyloidogenic and/or amyloidolytic via selection of alternative BACE1 cleavage sites.

Authors+Show Affiliations

From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-Nishi 6, Kita-ku, Sapporo 060-0812, Japan.From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-Nishi 6, Kita-ku, Sapporo 060-0812, Japan.From the Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-Nishi 6, Kita-ku, Sapporo 060-0812, Japan tsuzuki@pharm.hokudai.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27687728

Citation

Kimura, Ayano, et al. "Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations Within the Aβ Sequence." The Journal of Biological Chemistry, vol. 291, no. 46, 2016, pp. 24041-24053.
Kimura A, Hata S, Suzuki T. Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. J Biol Chem. 2016;291(46):24041-24053.
Kimura, A., Hata, S., & Suzuki, T. (2016). Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. The Journal of Biological Chemistry, 291(46), 24041-24053.
Kimura A, Hata S, Suzuki T. Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations Within the Aβ Sequence. J Biol Chem. 2016 Nov 11;291(46):24041-24053. PubMed PMID: 27687728.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. AU - Kimura,Ayano, AU - Hata,Saori, AU - Suzuki,Toshiharu, Y1 - 2016/09/29/ PY - 2016/06/21/received PY - 2016/09/21/revised PY - 2016/10/1/pubmed PY - 2017/5/26/medline PY - 2016/10/1/entrez KW - Alzheimer disease KW - amyloid precursor protein (APP) KW - amyloid-β (Aβ) KW - secretase KW - β-secretase 1 (BACE1) SP - 24041 EP - 24053 JF - The Journal of biological chemistry JO - J Biol Chem VL - 291 IS - 46 N2 - β-Site APP-cleaving enzyme 1 (BACE1) cleaves amyloid β-protein precursor (APP) at the bond between Met671 and Asp672 (β-site) to generate the carboxyl-terminal fragment (CTFβ/C99). BACE1 also cleaves APP at another bond between Thr681 and Gln682 (β'-site), yielding CTFβ'/C89. Cleavage of CTFβ/C99 by γ-secretase generates Aβ(1-XX), whereas cleavage of CTFβ'/C89 generates Aβ(11-XX). Thus, β'-site cleavage by BACE1 is amyloidolytic rather than amyloidogenic. β' cleavage of mouse APP is more common than the corresponding cleavage of human APP. We found that the H684R substitution within human Aβ, which replaces the histidine in the human protein with the arginine found at the corresponding position in mouse, facilitated β' cleavage irrespective of the species origin of BACE1, thereby significantly increasing the level of Aβ(11-XX) and decreasing the level of Aβ(1-XX). Thus, amino acid substitutions within the Aβ sequence influenced the selectivity of alternative β- or β'-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 Aβ(11-40) generation, whereas the protective Icelandic mutation (A673T) increases generation of Aβ(11-40). Thus, A673T promotes β' cleavage of APP and protects subjects against AD. In addition, CTFβ/C99 was cleaved by excess BACE1 activity to generate CTFβ'/C89, followed by Aβ(11-40), even if APP harbored pathogenic mutations. The resultant Aβ(11-40) was more metabolically labile in vivo than Aβ(1-40). Our analysis suggests that some FAD mutations in APP are amyloidogenic and/or amyloidolytic via selection of alternative BACE1 cleavage sites. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/27687728/Alternative_Selection_of_β_Site_APP_Cleaving_Enzyme_1__BACE1__Cleavage_Sites_in_Amyloid_β_Protein_Precursor__APP__Harboring_Protective_and_Pathogenic_Mutations_within_the_Aβ_Sequence_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)34674-3 DB - PRIME DP - Unbound Medicine ER -