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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 5; pp. 2092 - 2096
• Main Authors: Busciglio, Jorge, Gabuzda, Dana H., Matsudaira, Paul, Yankner, Bruce A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.03.1993; National Acad Sciences
• Subjects: Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - metabolism; Amyloids; Animals; Antibodies; Astrocytes; Astrocytes - metabolism; beta -amyloid; Biochemistry and metabolism; Biological and medical sciences; brain; Cells, Cultured; Central nervous system; Cercopithecus aethiops; COS cells; Fundamental and applied biological sciences. Psychology; Gels; glia; Golgi Apparatus - metabolism; In Vitro Techniques; Lysosomes - metabolism; man; Molecular Sequence Data; Neurons; Neurons - metabolism; Peptide Fragments - metabolism; Proteins; Quaternary ammonium compounds; Recombinant Proteins - metabolism; Secretion; Secretory pathway; Solubility; Time Factors; Transfection; Vertebrates: nervous system and sense organs; Cell culture; Glial cell; Molecular processing; Rat; Secretion; Rodentia; Central nervous system; Mechanism; Amyloid precursor protein; Golgi apparatus; Vertebrata; Regulation(control); Specificity; Mammalia; Cell line; β Amyloid protein; Animal; Brain (vertebrata)
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.5.2092

The cellular mechanism underlying the generation of β-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 β-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the β-amyloid N terminus. The β-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of β-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of β-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 β-amyloid than any other cell type examined. These results suggest that β-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of β-amyloid production in the brain.