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Full-length and truncated Alzheimer amyloid precursors in chromaffin granules: solubilization of membrane amyloid precursor is mediated by an enzymatic mechanism.
- Source :
-
Journal of neurochemistry [J Neurochem] 1995 May; Vol. 64 (5), pp. 2140-6. - Publication Year :
- 1995
-
Abstract
- The amyloid beta peptide (A beta) of Alzheimer disease is derived from the proteolytic processing of the amyloid precursor proteins (APPs), which are considered type I transmembrane proteins. Here we report that the soluble fraction of isolated adrenal medullary chromaffin granules (CG), a model neuronal secretory vesicle system, contains an antigen that immunochemically and on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was indistinguishable from full-length APP. A truncated APP fragment with intact A beta sequence was also detected in the soluble fraction of CG. In vitro experiments showed that full-length APP was solubilized from CG membranes at 37 degrees C as a function of pH, with a peak of activity between pH 8.5 and pH 9.0. Solubilization of full-length APP was inhibited by several protease inhibitors, including aprotinin, cystatin, and iodoacetamide, by the divalent cations Ca2+ and Zn2+, and by preheating of the membranes. These results are consistent with and suggest the involvement of an enzymatic mechanism in the solubilization of potentially amyloidogenic full-length APP. Production of A beta from a transmembrane APP predicts a proteolytic cleavage within the lipid bilayer, a site relatively inaccessible to proteases. Thus, the detected soluble, potentially amyloidogenic, full-length APP may be a substrate for the proteases producing A beta. The detection of soluble APP with intact A beta sequence in secretory vesicles is consistent with the extracellular topology of amyloid depositions.
- Subjects :
- Amyloid beta-Protein Precursor isolation & purification
Amyloid beta-Protein Precursor metabolism
Animals
Calcium pharmacology
Cations, Divalent
Cattle
Cysteine Endopeptidases metabolism
Electrophoresis, Polyacrylamide Gel
Endopeptidases metabolism
Hot Temperature
Hydrogen-Ion Concentration
Intracellular Membranes chemistry
Protease Inhibitors pharmacology
Serine Endopeptidases metabolism
Solubility
Zinc pharmacology
Adrenal Medulla ultrastructure
Amyloid beta-Protein Precursor analysis
Chromaffin Granules chemistry
Intracellular Membranes enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3042
- Volume :
- 64
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 7722498
- Full Text :
- https://doi.org/10.1046/j.1471-4159.1995.64052140.x