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Cited by 205

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid β‐Proteina

SELKOE, D. J., YAMAZAKI, T., CITRON, M., PODLISNY, M. B., KOO, E. H., TEPLOW, D. B., HAASS, C.·1996·Annals of the New York Academy of Sciences
DOI 10.1111/j.1749-6632.1996.tb34401.x
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Abstract

The amyloid β‐protein (Aβ) is a proteolytic fragment of the β‐amyloid precursor protein (βAPP). We previously reported the constitutive secretion of Aβ peptides from a variety of cells expressing βAPP under normal culture conditions. These endogenously produced Aβpeptides have heterogeneous N‐and C‐termini that vary as a function of βAPP missense mutations. Treatment of Aβ‐secreting cells with agents that alter intravesicular pH showed that an acidic compartment is required for proper Aβ generation. One such compartment appears to be the endosome. Immunolabeling of cell‐surface βAPP in living neurons and non‐neuronal cells directly demonstrated the endocytosis of the protein and its rapid recycling (within 5–10 minutes) to the cell surface, as well as the trafficking of some βAPP to lysosomes. Expression of βAPP with various deletions of the cytoplasmic domain, including the NPTY motif, leads to decreased internalization and an associated decrease in the production of Aβ peptides that begin at the usual asp 1 start site. These and other data suggest that Aβ production begins with cleavage of βAPP by a still unknown protease(s) (β‐secretase[s] at the met‐asp bond preceding the Aβ N‐terminus and that this occurs in part in early endosomes. To characterize the substrate requirements of β‐secretase, βAPP was mutagenized by placing stop codons within or at the end of the transmembrane domain or substituting other amino acids for the wild‐type met and asp at the P 1 and P 1' positions. These experiments showed that proper β‐secretase cleavage requires the precursor to be membrane‐anchored and is highly sequence specific; most substitutions at met or asp substantially decrease Aβ production. Analogous mutagenesis experiments around the Aβ C‐terminus revealed that the unknown protease(s) cleaving here (“γ‐secretase[s]”) does not show such specificity. Cells secreting Aβ may also be useful for examining the critical issue of the aggregation of Aβ into its neurotoxic polymeric form under physiological conditions. In this regard, we have found that AβAPP‐expressing CHO cells show aggregation of 10‐20% of their secreted Aβ peptides into SDS‐stable dimers, trimers and sometimes tetramers under normal culture conditions. The identity of these small multimers was confirmed by extensive immunochemical characterization and radiosequencing. They are present at  100‐500 pM levels in conditioned medium of CHO transfectants. Using this endogenous Aβ aggregating system, we have begun to examine variables that influence aggregation and compounds which may retard it. In conclusion, studies of the regulation of Aβ production and aggregation in cell culture can provide information under physiological conditions that can complement analyses of these processes in vivo.

Overview

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Registry

Crossref · 10.1111/j.1749-6632.1996.tb34401.x

Cites

4 of 4 references verified0 citation errors · 0 not checkable

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This paper’s full text isn’t openly available, 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?

  • APPswe exhibits much higher affinity to BACE1 compared with WT APP, and APPswe may be cleaved by BACE1 at TGN whereas WT APP may be cleaved at endosome compartments.

    “it is reported that APPswe exhibits a much higher affinity to BACE1 as compared with the WT APP, and APPswe may be cleaved by BACE1 at the TGN, whereas WT APP may be cleaved at the endosome compartments (Haass et al., 1995; Selkoe et al., 1996; Thinakaran and Koo, 2008).”

    From VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology (2011) · cites this paper as Selkoe et al., 1996

  • Aβ is one of the proteolytic products of APP metabolism generated from concerted cleavage at the N- and C-terminal site by β and γ secretase.

    “A␤ is one of the proteolytic products of APP metabolism generated from the concerted cleavage at the N-and C-terminal site of the molecule by ␤ and ␥ secretase, respectively”

    From Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein (2002) · cites this paper as Selkoe et al., 1996

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 15

  1. 10.1038/357500a0 · DOI
  2. 10.1007/BF00965926 · DOI
  3. 10.1126/science.1738847 · DOI
  4. 10.1073/pnas.89.6.2252 · DOI
  5. 10.1126/science.2111583 · DOI
  6. 10.1126/science.1691865 · DOI
  7. Koo E. H., 1994, Evidence that production and release of amyloid β‐protein involves the endocytic pathway., J. Biol. Chem., 269, 17386, 10.1016/S0021-9258(17)32449-3 · DOI · Paper page
  8. 10.1038/361260a0 · DOI
  9. Haass C., 1993, β‐Amyloid peptide and a 3‐kDa fragment are derived by distinct cellular mechanisms, J. Biol. Chem., 268, 3021, 10.1016/S0021-9258(18)53650-4 · DOI
  10. 10.1073/pnas.90.5.2092 · DOI · Paper page
  11. 10.1016/S0021-9258(17)32503-6 · DOI
  12. 10.1126/science.8191290 · DOI · Paper page
  13. 10.1073/pnas.91.25.11993 · DOI · Paper page
  14. 10.1073/pnas.91.4.1564 · DOI
  15. 10.1083/jcb.128.4.537 · DOI

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Metadata

Authors
SELKOE, D. J., YAMAZAKI, T., CITRON, M., PODLISNY, M. B., KOO, E. H., TEPLOW, D. B., & HAASS, C.
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
1996-01
Volume
777
Issue
1
Pages
57-64
ISSN
  • 0077-8923
  • 1749-6632
DOI
10.1111/j.1749-6632.1996.tb34401.x
Cited by
205
References
4
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 4003 d)

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