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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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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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