Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments
- PMID: 1608449
- DOI: 10.1038/357500a0
Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments
Abstract
Progressive cerebral deposition of the amyloid beta-peptide is an early and invariant feature of Alzheimer's disease. The beta-peptide is released by proteolytic cleavages from the beta-amyloid precursor protein (beta APP), a membrane-spanning glycoprotein expressed in most mammalian cells. Normal secretion of beta APP involves a cleavage in the beta-peptide region, releasing the soluble extramembranous portion and retaining a 10K C-terminal fragment in the membrane. Because this secretory pathway precludes beta-amyloid formation, we searched for an alternative proteolytic processing pathway that can generate beta-peptide-bearing fragments from full-length beta APP. Incubation of living human endothelial cells with a beta APP antibody revealed reinternalization of mature beta APP from the cell surface and its targeting to endosomes/lysosomes. After cell-surface biotinylation, full-length biotinylated beta APP was recovered inside the cells. Purification of lysosomes directly demonstrated the presence of mature beta APP and an extensive array of beta-peptide-containing proteolytic products. Our results define a second processing pathway for beta APP and suggest that it may be responsible for generating amyloid-bearing fragments in Alzheimer's disease.
Similar articles
-
Processing of the Alzheimer's disease amyloid precursor protein in Pichia pastoris: immunodetection of alpha-, beta-, and gamma-secretase products.Biochemistry. 1998 Oct 20;37(42):14958-65. doi: 10.1021/bi981063l. Biochemistry. 1998. PMID: 9778373
-
Intracellular generation of amyloid beta-protein from amyloid beta-protein precursor fragment by direct cleavage with beta- and gamma-secretase.Biochem Biophys Res Commun. 1996 Jan 5;218(1):238-42. doi: 10.1006/bbrc.1996.0042. Biochem Biophys Res Commun. 1996. PMID: 8573139
-
Production of Alzheimer 4kDa beta-amyloid peptide requires the C-terminal cytosolic domain of the amyloid precursor protein.Biochem Biophys Res Commun. 1994 Nov 15;204(3):1371-80. doi: 10.1006/bbrc.1994.2615. Biochem Biophys Res Commun. 1994. PMID: 7980616
-
beta-Amyloid, protein processing and Alzheimer's disease.Arzneimittelforschung. 1995 Mar;45(3A):398-402. Arzneimittelforschung. 1995. PMID: 7763333 Review.
-
[Recent advances in Alzheimer's disease research--amyloid precursor protein trafficking, processing, and mutations in Alzheimer's disease linked genes].Hokkaido Igaku Zasshi. 1997 Jan;72(1):3-11. Hokkaido Igaku Zasshi. 1997. PMID: 9086357 Review. Japanese.
Cited by
-
Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts.J Neurosci. 2013 Jul 3;33(27):11169-83. doi: 10.1523/JNEUROSCI.4704-12.2013. J Neurosci. 2013. PMID: 23825420 Free PMC article.
-
Natural compounds may open new routes to treatment of amyloid diseases.Neurotherapeutics. 2013 Jul;10(3):429-39. doi: 10.1007/s13311-013-0192-7. Neurotherapeutics. 2013. PMID: 23670234 Free PMC article. Review.
-
Search for amyloid-binding proteins by affinity chromatography.Methods Mol Biol. 2012;849:213-23. doi: 10.1007/978-1-61779-551-0_15. Methods Mol Biol. 2012. PMID: 22528093 Free PMC article.
-
AβPP processing results in greater toxicity per amount of Aβ1-42 than individually expressed and secreted Aβ1-42 in Drosophila melanogaster.Biol Open. 2016 Aug 15;5(8):1030-9. doi: 10.1242/bio.017194. Biol Open. 2016. PMID: 27387531 Free PMC article.
-
Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-beta degrading enzyme neprilysin.Mol Biol Cell. 2007 Sep;18(9):3591-600. doi: 10.1091/mbc.e07-01-0035. Epub 2007 Jul 11. Mol Biol Cell. 2007. PMID: 17626163 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
