CoChat
Sign Up
Cited by 356Alzheimer's disease research and treatmentsLipid Membrane Structure and BehaviorLysosomal Storage Disorders Research

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 access
Cordy, Joanna M., Hussain, Ishrut, Dingwall, Colin, Hooper, Nigel M., Turner, Anthony J.·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1635130100PMC PMC208827
Open this paper in CoChat — free account

Abstract

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.

Overview

Integrity signals

Registry

Crossref · 10.1073/pnas.1635130100

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 36 references

Research works printed but not linked: 1

  1. Refolo, L. M., Malester, B., LaFrancois, J., Bryant-Thomas, T., Wang, R., Tint, G. S., Sambamurti, K., Duff, K. & Pappolla, M. A. (2000) Neurobiol. Dis. 4, 321–331.

Cited by

Sorted by citations

Related

See all

Metadata

Authors
Cordy, J. M., Hussain, I., Dingwall, C., Hooper, N. M., & Turner, A. J.
Affiliations
University of Leeds (GB)
ORCID
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
DOI
10.1073/pnas.1635130100
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review