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BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis.
J Neurosci. 2017 07 19; 37(29):6915-6925.JN

Abstract

Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, β-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu11 site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited γ-secretase cleavage of the mutant C99 to generate Aβ, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT β-site APP cleaving enzyme 1 (BACE1) is essential for amyloid β protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid β precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited γ-secretase cleavage of the mutant C99 to generate amyloid β protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

Authors+Show Affiliations

Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada weihong@mail.ubc.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28626014

Citation

Zhang, Shuting, et al. "BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 37, no. 29, 2017, pp. 6915-6925.
Zhang S, Wang Z, Cai F, et al. BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. J Neurosci. 2017;37(29):6915-6925.
Zhang, S., Wang, Z., Cai, F., Zhang, M., Wu, Y., Zhang, J., & Song, W. (2017). BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 37(29), 6915-6925. https://doi.org/10.1523/JNEUROSCI.0340-17.2017
Zhang S, et al. BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. J Neurosci. 2017 07 19;37(29):6915-6925. PubMed PMID: 28626014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. AU - Zhang,Shuting, AU - Wang,Zhe, AU - Cai,Fang, AU - Zhang,Mingming, AU - Wu,Yili, AU - Zhang,Jing, AU - Song,Weihong, Y1 - 2017/06/16/ PY - 2017/02/06/received PY - 2017/06/02/revised PY - 2017/06/08/accepted PY - 2017/6/20/pubmed PY - 2017/8/19/medline PY - 2017/6/20/entrez KW - Alzheimer's disease KW - BACE1 SP - 6915 EP - 6925 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 37 IS - 29 N2 - Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, β-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu11 site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited γ-secretase cleavage of the mutant C99 to generate Aβ, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT β-site APP cleaving enzyme 1 (BACE1) is essential for amyloid β protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid β precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited γ-secretase cleavage of the mutant C99 to generate amyloid β protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/28626014/BACE1_Cleavage_Site_Selection_Critical_for_Amyloidogenesis_and_Alzheimer's_Pathogenesis_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=28626014 DB - PRIME DP - Unbound Medicine ER -