Generation of Beta-Amyloid in the Secretory Pathway in Neuronal and Nonneuronal Cells

Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2092-6. doi: 10.1073/pnas.90.5.2092.

Abstract

The cellular mechanism underlying the generation of beta-amyloid in Alzheimer disease and its relationship to the normal metabolism of the amyloid precursor protein are unknown. In this report, we show that 3- and 4-kDa peptides derived from amyloid precursor protein are normally secreted. Epitope mapping and radiolabel sequence analysis suggest that the 4-kDa peptide is closely related to full-length beta-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the beta-amyloid N terminus. The beta-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of beta-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of beta-amyloid-related peptides occurs in a wide variety of cell types, but which peptides are produced and their absolute levels are dependent on cell type. Human astrocytes generated higher levels of beta-amyloid than any other cell type examined. These results suggest that beta-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of beta-amyloid production in the brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Golgi Apparatus / metabolism
  • In Vitro Techniques
  • Lysosomes / metabolism
  • Molecular Sequence Data
  • Neurons / metabolism*
  • Peptide Fragments / metabolism
  • Recombinant Proteins / metabolism
  • Solubility
  • Time Factors
  • Transfection

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • Recombinant Proteins