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Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

Ehehalt, Robert, Keller, Patrick, Haass, Christian, Thiele, Christoph, Simons, Kai·2003·The Journal of Cell Biology
DOI 10.1083/jcb.200207113PMC PMC2172747
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Abstract

Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.

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Crossref · 10.1083/jcb.200207113

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  • Directing APP to rafts enhances β-cleavage and Aβ generation.

    “such an interaction may help explain the observations that directing APP to rafts enhances ␤-cleavage and A␤ generation (13).”

    From The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate (2005) · cites this paper as [13]

    The Results section on antibody-induced cross-linking (page not provided) reports increased Aβ secretion when APP and BACE1 were copatched in rafts. The Discussion says this clustering can promote β-cleavage, but also states that partitioning APP and BACE1 into rafts alone is insufficient: cleavage normally depends on endocytosis. The claim omits that distinction and implies that directing APP to rafts by itself produces both effects. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Amyloidogenic processing of APP in cultured cells occurs primarily in cholesterol-rich membrane domains.

    “Our findings contribute to literature, demonstrating that amyloidogenic processing of APP in cultured cells occurs primarily in cholesterol-rich membrane domains (15, 62)”

    From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [15]

    The Results show that cholesterol depletion in cultured N2a cells inhibits β-cleavage and Aβ production. The Discussion supports a crucial role for lipid rafts but describes cleavage within rafts as a proposed model and says more work is needed to establish direct dependence on the raft environment. Thus, the paper does not demonstrate that processing occurs primarily within those domains. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • LRP potentially acts as a scaffolding complex in rafts for APP and for BACE.

    “Thus, LRP, which is highly enriched in rafts, potentially acts as a scaffolding complex in rafts for APP and for BACE; such an interaction may help explain the observations that directing APP to rafts enhances ␤-cleavage and A␤ generation (13).”

    From The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate (2005) · cites this paper as [13]

  • Outside lipid rafts, APP is processed at the plasma membrane by α-secretase and -secretases producing sAPP-α via the non-amyloidogenic pathway.

    “Outside of lipid rafts, APP is processed at the PM by α-secretase and -secretases producing sAPP-α (non-amyloidogenic pathway) [38–40].”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [39]

  • The pair correlation ranged from 10 to 15 for APP, β-secretase, and γ-secretase, while the pair correlation for α-secretase was <3.

    “The pair correlation (a unitless number) ranged from 10 to 15 for APP, β-secretase, and γ-secretase, while the pair correlation for α-secretase was <3, a value typical for little or no pair correlation, a result also consistent with previous experiments in DRMs (15).”

    From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [15]

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Citations

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Metadata

Authors
Ehehalt, R., Keller, P., Haass, C., Thiele, C., & Simons, K.
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2003-01-06
Volume
160
Issue
1
Pages
113-123
ISSN
  • 1540-8140
  • 0021-9525
DOI
10.1083/jcb.200207113
PMC
PMC2172747
Cited by
932
References
3
Language
en

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