{"doi":"10.1111/ejn.12235","title":"Amyloid‐β protein (Aβ) Glu11 is the major β‐secretase site of β‐site amyloid‐β precursor protein‐cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis","abstract":"<jats:title>Abstract</jats:title><jats:p>Cleavage of amyloid‐β precursor protein (<jats:styled-content style=\"fixed-case\">APP</jats:styled-content>) at the Asp1 β‐secretase site of the amyloid‐β protein (Aβ) domain by β‐site Aβ precursor protein‐cleaving enzyme 1 (<jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (<jats:styled-content style=\"fixed-case\">AD</jats:styled-content>) brain. In this study, we found that Aβ Glu11 is the major β‐secretase site for cleavage of <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> by <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 to generate soluble secreted <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> (<jats:styled-content style=\"fixed-case\">sAPP</jats:styled-content>β)<jats:sup>606</jats:sup> and the C‐terminal membrane‐bound fragment (<jats:styled-content style=\"fixed-case\">CTF</jats:styled-content>)β product C89. Cleavage of C89 by γ‐secretase resulted in truncated Aβ generation in a non‐amyloidogenic pathway. A familial <jats:styled-content style=\"fixed-case\">AD</jats:styled-content>‐associated Swedish <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> mutation adjacent to Aβ Asp1 shifted the major <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> β‐secretase cleavage site from Aβ Glu11 to Asp1, resulting in significant increases in <jats:styled-content style=\"fixed-case\">sAPP</jats:styled-content>β596 and <jats:styled-content style=\"fixed-case\">CTF</jats:styled-content>β C99 generation and the C99/89 ratio, in turn leading to increased Aβ production in cultured cells <jats:italic>in vitro</jats:italic> and transgenic <jats:styled-content style=\"fixed-case\">AD</jats:styled-content> model mouse brains <jats:italic>in vivo</jats:italic>. Furthermore, increased <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 expression facilitated <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> being processed by the β‐secretase processing pathway rather than the α‐secretase pathway, leading to more Aβ production. Our results suggest that potentiating <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 cleavage of <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased Aβ production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 expression and β‐secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection.</jats:p>","journal":"European Journal of Neuroscience","year":2013,"id":612366,"datarank":0.6952093482344455,"base_score":4.634728988229636,"endowment":4.634728988229636,"self_citation_contribution":0.6952093482344455,"citation_network_contribution":0.0,"self_endowment_contribution":0.6952093482344455,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":102,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":677843,"name":"Zhe Wang","orcid":"0000-0001-9232-3699","position":1,"is_corresponding":false},{"id":494397,"name":"Ruitao Wang","orcid":"0000-0002-4703-7367","position":2,"is_corresponding":false},{"id":376312,"name":"Xiaozhu Zhang","orcid":"0000-0003-3816-1478","position":3,"is_corresponding":false},{"id":1109964,"name":"Shuting Zhang","orcid":"0000-0003-1627-0438","position":4,"is_corresponding":false},{"id":1366871,"name":"Yili Wu","orcid":"0000-0002-2369-6974","position":5,"is_corresponding":false},{"id":293805,"name":"Matthias Staufenbiel","orcid":null,"position":6,"is_corresponding":false},{"id":858347,"name":"Fang Cai","orcid":null,"position":7,"is_corresponding":false},{"id":371197,"name":"Weihong Song","orcid":"0000-0001-9928-889X","position":8,"is_corresponding":false},{"id":1257620,"name":"Yu Deng","orcid":"0000-0002-3264-0809","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Amyloid‐β protein (Aβ) Glu11 is the major β‐secretase site of β‐site amyloid‐β precursor protein‐cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis","abstract":"<jats:title>Abstract</jats:title><jats:p>Cleavage of amyloid‐β precursor protein (<jats:styled-content style=\"fixed-case\">APP</jats:styled-content>) at the Asp1 β‐secretase site of the amyloid‐β protein (Aβ) domain by β‐site Aβ precursor protein‐cleaving enzyme 1 (<jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1) is required for the generation of Aβ, a central component of neuritic plaques in the Alzheimer's disease (<jats:styled-content style=\"fixed-case\">AD</jats:styled-content>) brain. In this study, we found that Aβ Glu11 is the major β‐secretase site for cleavage of <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> by <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 to generate soluble secreted <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> (<jats:styled-content style=\"fixed-case\">sAPP</jats:styled-content>β)<jats:sup>606</jats:sup> and the C‐terminal membrane‐bound fragment (<jats:styled-content style=\"fixed-case\">CTF</jats:styled-content>)β product C89. Cleavage of C89 by γ‐secretase resulted in truncated Aβ generation in a non‐amyloidogenic pathway. A familial <jats:styled-content style=\"fixed-case\">AD</jats:styled-content>‐associated Swedish <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> mutation adjacent to Aβ Asp1 shifted the major <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> β‐secretase cleavage site from Aβ Glu11 to Asp1, resulting in significant increases in <jats:styled-content style=\"fixed-case\">sAPP</jats:styled-content>β596 and <jats:styled-content style=\"fixed-case\">CTF</jats:styled-content>β C99 generation and the C99/89 ratio, in turn leading to increased Aβ production in cultured cells <jats:italic>in vitro</jats:italic> and transgenic <jats:styled-content style=\"fixed-case\">AD</jats:styled-content> model mouse brains <jats:italic>in vivo</jats:italic>. Furthermore, increased <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 expression facilitated <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> being processed by the β‐secretase processing pathway rather than the α‐secretase pathway, leading to more Aβ production. Our results suggest that potentiating <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 cleavage of <jats:styled-content style=\"fixed-case\">APP</jats:styled-content> at both the Asp1 and Glu11 sites, or shifting the cleavage from the Glu11 site to the Asp1 site, could result in increased Aβ production and facilitate neuritic plaque formation. Our study provides new insights into how alteration of <jats:styled-content style=\"fixed-case\">BACE</jats:styled-content>1 expression and β‐secretase cleavage site selection could contribute to Alzheimer pathogenesis and the pharmaceutical potential of modulating BACE1 expression and its cleavage site selection.</jats:p>","is_dataset_classified":null,"base_score":4.634728988229636,"endowment":4.634728988229636,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23773065","pmcid":null,"openalex_id":"https://openalex.org/W2093356656","authors":[],"funders":[{"funder_name":"Canadian Institutes of Health Research","grant_id":"TAD-117948","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"MOP-97825","title":null}],"total_grants":2,"fwci":2.8247,"citation_percentile":0.90831145,"influential_citations":0,"citation_trend":[{"year":2013,"count":4},{"year":2014,"count":5},{"year":2015,"count":3},{"year":2016,"count":5},{"year":2017,"count":8},{"year":2018,"count":6},{"year":2019,"count":7},{"year":2020,"count":7},{"year":2021,"count":4},{"year":2022,"count":11},{"year":2023,"count":9},{"year":2024,"count":13},{"year":2025,"count":16},{"year":2026,"count":4}],"oa_status":"closed","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fejn.12235","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/ejn.12235","host_type":"publisher"},{"url":"https://doi.org/10.1111/ejn.12235","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23773065","host_type":"repository"}],"fields_of_study":["Alzheimer's disease research and treatments","Cholinesterase and Neurodegenerative Diseases","Computational Drug Discovery Methods","Chemistry","Medicine","Biology","Alzheimer Disease","Amyloid Precursor Protein Secretases","Amyloid beta-Peptides","Amyloid beta-Protein Precursor","Animals","Aspartic Acid Endopeptidases","Cells, Cultured","Mice","Mice, Mutant Strains","Mice, Transgenic"],"mesh_terms":["Alzheimer Disease","Animals","Cells, Cultured","Mice, Mutant Strains","Mice, Transgenic","Amyloid beta-Peptides","Aspartic Acid Endopeptidases","Amyloid beta-Protein Precursor","Mice","Amyloid Precursor Protein Secretases"],"keywords":["Amyloid precursor protein","Amyloid precursor protein secretase","Cleavage (geology)","Alpha secretase","Chemistry","Senile plaques","P3 peptide","BACE1-AS","Cell biology","Biochemistry","Alzheimer's disease","Molecular biology","Genetically modified mouse","Biology","Transgene","Gene","Medicine","Internal medicine"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T03:06:08.533796Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}