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(NAS Colloquium) Proteolytic Processing and Physiological Regulation (1999) / Chapter Skim
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Cellular mechanisms of ß-amyloid production and secretion
Pages 11049-11053

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From page 11049...
... APP695, the splicing variant lacking the Kunitz domain, was preferentially expressed in neuronal tissue, leading to the speculation that the production of A,B from APP could be regulated by a protease that is inhibited by this domain. The demonstration that a secreted, soluble form of APP was functionally identical to a previously isolated serine protease inhibitor called protease nexin II (5)
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From page 11050...
... This observation provided, not only a mechanistic explanation for a pathogenic mutation, but also a cellular system, relevant to the underlying disease model, in which to study pharmacological agents that can selectively inhibit the formation of Al3. A specific and potent inhibitor of vacuolar ATPases, bafilomycin, was shown to inhibit ,8-sAPP selectively, but not c~-sAPP, both from HEK293 cells transfected with APP Swedish mutants and from fetal neuronal cultures (20~.
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From page 11051...
... However, it has been suggested that A,B 1-40 is produced at greater proximity to the cell surface than is Al3 1-42 (40~; if this suggestion is accurate, variations in intracellular compound levels in different intracellular compartments may explain the differential inhibitory susceptibilities with some of these compounds. Although the peptide aldehydes seem to point to the role of an intracellular cysteine or serine protease as pivotal to ~y-secretase processing of CTFs, direct evidence for such an enzyme target for these compounds is still lacking.
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From page 11052...
... x-42 forms were then analyzed in the CM of cells transfected with these mutant forms. Although position 45 was identified as being critical for - 42 cleavage, there was little specificity at the y-cleavage sites; although there were alterations in the relative ratios, total Al3 formation was relatively unaffected by the scanning mutagenesis, suggesting that the precise identity of the amino acid residues at or near the y-cleavage sites was not critical to total cleavage.
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From page 11053...
... Colloquium Paper: Sinha and Lieberburg 27. Dovey, H
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Key Terms

  • cleavage site
  • neuronal cultures
  • missense mutations
  • phorbol esters
  • cells transfected

  • swedish mutation
  • amino acids
  • mutated protein
  • serine protease
  • acid residues

  • neuronal cells
  • fetal neuronal
  • vacuolar atpases
  • conditioned medium
  • true candidate

  • scanning mutagenesis
  • pharmacological agents
  • acidic intracellular
  • central nervous
  • cellular enzyme

  • cell surface
  • amino acid
  • stimulated release
  • fusion proteins
  • intracellular cysteine

  • presenilin mutants
  • separate missense
  • chinese hamster
  • cell lines
  • protease inhibitor


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