The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein
Open accessAbstract
β-Secretase (BACE, Asp-2) is a transmembrane aspartic proteinase responsible for cleaving the amyloid precursor protein (APP) to generate the soluble ectodomain sAPPβ and its C-terminal fragment CTFβ. CTFβ is subsequently cleaved by γ-secretase to produce the neurotoxic/synaptotoxic amyloid-β peptide (Aβ) that accumulates in Alzheimer's disease. Indirect evidence has suggested that amyloidogenic APP processing may preferentially occur in lipid rafts. Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent. To investigate further the significance of lipid rafts in APP processing, a glycosylphosphatidylinositol (GPI) anchor has been added to BACE, replacing the transmembrane and C-terminal domains. The GPI anchor targets the enzyme exclusively to lipid raft domains. Expression of GPIBACE substantially up-regulates the secretion of both sAPPβ and amyloid-β peptide over levels observed from cells overexpressing wild-type BACE. This effect was reversed when the lipid rafts were disrupted by depleting cellular cholesterol levels. These results suggest that processing of APP to the amyloid-β peptide occurs predominantly in lipid rafts and that BACE is the rate-limiting enzyme in this process. The processing of the APP 695 isoform by GPI-BACE was up-regulated 20-fold compared with wild-type BACE, whereas only a 2-fold increase in the processing of APP 751/770 was seen, implying a differential compartmentation of the APP isoforms. Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased β-amyloid production.
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“APOE isoforms likely influence Aβ production by modulating lipid metabolism and the lipid composition of cellular membranes, with APOE4 promoting amyloidogenic APP cleavage and Aβ production more than APOE3 [8–10].”
In the citing paper
“APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms: 1) influencing APP processing via effects on lipid metabolism [8–10], and 2) modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes [11, 12].”
In the citing paper
“Aβ peptides are produced primarily by neurons via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases (amyloidogenic pathway) at lipid rafts in the plasma membrane (PM) [35–37].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [36]
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Research works printed but not linked: 1
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Trafficking and Proteolytic Processing of APP
Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075
Modulation of neurodegeneration by molecular chaperones
Muchowski, P. J., & Wacker, J. L. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1587 · Cited by 1,043
Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Domínguez, L., Shea, J., Dokholyan, N. V., Simone, A. D., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 680
Vassar, R., Kovacs, D. M., Yan, R., & Wong, P. C. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3657-09.2009 · Cited by 577
The Alzheimer's disease Beta-secretase enzyme, BACE1
Cole, S. L., & Vassar, R. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-22 · Cited by 550
Metadata
- Authors
- Cordy, J. M., Hussain, I., Dingwall, C., Hooper, N. M., & Turner, A. J.
- Affiliations
- University of Leeds (GB)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-09-22
- Volume
- 100
- Issue
- 20
- Pages
- 11735-11740
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC208827
- OpenAlex
- W2160524771
- Cited by
- 356
- References
- 36
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 5 · 2017: 10 · 2016: 9 · 2015: 5 · 2014: 12 · 2013: 16 · 2012: 30
- FWCI
- 12.29
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- beta-secretase, BACE, amyloid precursor protein, lipid rafts, GPI anchoring, amyloid-beta production, APP processing, cholesterol depletion, APP isoforms, Alzheimer's disease, SH-SY5Y cells
- MeSH terms
- Amino Acid Sequence, Cholesterol, Humans, Hydrolysis, Molecular Sequence Data, Endopeptidases, Protein Processing, Post-Translational, Tumor Cells, Cultured, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Glycosylphosphatidylinositols, Lipid Metabolism, Amyloid Precursor Protein Secretases
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