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Loss of cleavage at β'-site contributes to apparent increase in β-amyloid peptide (Aβ) secretion by β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein.
J Biol Chem. 2011 Jul 22; 286(29):26166-77.JB

Abstract

Several lines of evidence implicate lipid raft microdomains in Alzheimer disease-associated β-amyloid peptide (Aβ) production. Notably, targeting β-secretase (β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)) exclusively to lipid rafts by the addition of a glycosylphosphatidylinositol (GPI) anchor to its ectodomain has been reported to elevate Aβ secretion. Paradoxically, Aβ secretion is not reduced by the expression of non-raft resident S-palmitoylation-deficient BACE1 (BACE1-4C/A (C474A/C478A/C482A/C485A)). We addressed this apparent discrepancy in raft microdomain-associated BACE1 processing of APP in this study. As previously reported, we found that expression of BACE1-GPI elevated Aβ secretion as compared with wild-type BACE1 (WTBACE1) or BACE1-4C/A. However, this increase occurred without any difference in the levels of APP ectodomain released following BACE1 cleavage (soluble APPβ), arguing against an overall increase in BACE1 processing of APP per se. Further analysis revealed that WTBACE1 cleaves APP at β- and β'-sites, generating +1 and +11 β-C-terminal fragments and secreting intact as well as N-terminally truncated Aβ. In contrast, three different BACE1-GPI chimeras preferentially cleaved APP at the β-site, mainly generating +1 β-C-terminal fragment and secreting intact Aβ. As a consequence, cells expressing BACE1-GPI secreted relatively higher levels of intact Aβ without an increase in BACE1 processing of APP. Markedly reduced cleavage at β'-site exhibited by BACE1-GPI was cell type-independent and insensitive to subcellular localization of APP or the pathogenic KM/NL mutant. We conclude that the apparent elevation in Aβ secretion by BACE1-GPI is mainly attributed to preferential cleavage at the β-site and failure to detect +11 Aβ species secreted by cells expressing WTBACE1.

Authors+Show Affiliations

Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21642424

Citation

Vetrivel, Kulandaivelu S., et al. "Loss of Cleavage at Β'-site Contributes to Apparent Increase in Β-amyloid Peptide (Aβ) Secretion By Β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) Processing of Amyloid Precursor Protein." The Journal of Biological Chemistry, vol. 286, no. 29, 2011, pp. 26166-77.
Vetrivel KS, Barman A, Chen Y, et al. Loss of cleavage at β'-site contributes to apparent increase in β-amyloid peptide (Aβ) secretion by β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein. J Biol Chem. 2011;286(29):26166-77.
Vetrivel, K. S., Barman, A., Chen, Y., Nguyen, P. D., Wagner, S. L., Prabhakar, R., & Thinakaran, G. (2011). Loss of cleavage at β'-site contributes to apparent increase in β-amyloid peptide (Aβ) secretion by β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein. The Journal of Biological Chemistry, 286(29), 26166-77. https://doi.org/10.1074/jbc.M111.260471
Vetrivel KS, et al. Loss of Cleavage at Β'-site Contributes to Apparent Increase in Β-amyloid Peptide (Aβ) Secretion By Β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) Processing of Amyloid Precursor Protein. J Biol Chem. 2011 Jul 22;286(29):26166-77. PubMed PMID: 21642424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of cleavage at β'-site contributes to apparent increase in β-amyloid peptide (Aβ) secretion by β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein. AU - Vetrivel,Kulandaivelu S, AU - Barman,Arghya, AU - Chen,Ying, AU - Nguyen,Phuong D, AU - Wagner,Steven L, AU - Prabhakar,Rajeev, AU - Thinakaran,Gopal, Y1 - 2011/06/03/ PY - 2011/6/7/entrez PY - 2011/6/7/pubmed PY - 2011/9/17/medline SP - 26166 EP - 77 JF - The Journal of biological chemistry JO - J Biol Chem VL - 286 IS - 29 N2 - Several lines of evidence implicate lipid raft microdomains in Alzheimer disease-associated β-amyloid peptide (Aβ) production. Notably, targeting β-secretase (β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)) exclusively to lipid rafts by the addition of a glycosylphosphatidylinositol (GPI) anchor to its ectodomain has been reported to elevate Aβ secretion. Paradoxically, Aβ secretion is not reduced by the expression of non-raft resident S-palmitoylation-deficient BACE1 (BACE1-4C/A (C474A/C478A/C482A/C485A)). We addressed this apparent discrepancy in raft microdomain-associated BACE1 processing of APP in this study. As previously reported, we found that expression of BACE1-GPI elevated Aβ secretion as compared with wild-type BACE1 (WTBACE1) or BACE1-4C/A. However, this increase occurred without any difference in the levels of APP ectodomain released following BACE1 cleavage (soluble APPβ), arguing against an overall increase in BACE1 processing of APP per se. Further analysis revealed that WTBACE1 cleaves APP at β- and β'-sites, generating +1 and +11 β-C-terminal fragments and secreting intact as well as N-terminally truncated Aβ. In contrast, three different BACE1-GPI chimeras preferentially cleaved APP at the β-site, mainly generating +1 β-C-terminal fragment and secreting intact Aβ. As a consequence, cells expressing BACE1-GPI secreted relatively higher levels of intact Aβ without an increase in BACE1 processing of APP. Markedly reduced cleavage at β'-site exhibited by BACE1-GPI was cell type-independent and insensitive to subcellular localization of APP or the pathogenic KM/NL mutant. We conclude that the apparent elevation in Aβ secretion by BACE1-GPI is mainly attributed to preferential cleavage at the β-site and failure to detect +11 Aβ species secreted by cells expressing WTBACE1. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/21642424/Loss_of_cleavage_at_β'_site_contributes_to_apparent_increase_in_β_amyloid_peptide__Aβ__secretion_by_β_secretase__BACE1__glycosylphosphatidylinositol__GPI__processing_of_amyloid_precursor_protein_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)48602-X DB - PRIME DP - Unbound Medicine ER -