Alzheimer's disease amyloid precursor protein (ApPP): proteolytic processing, secretases and βA4 amyloid production
- 1 January 1994
- journal article
- research article
- Published by Taylor & Francis in Amyloid
- Vol. 1 (4) , 263-280
- https://doi.org/10.3109/13506129409146118
Abstract
The major component of Alzheimer's disease amyloid is the 4 kDa peptide βA4 which is produced from an integral membrane protein (amyloid beta precursor protein, AβPP) by proteolytic processing. Cleavage of the βA4 domain from the precursor protein is part of a complex process which results in the release of AβPP from the membrane. AβPP is released by cleavage within the βA4 domain by a putative a-secretase. However, other cleavage sites exist, one of them being located at the NH2-terminus of βA4. Several factors such as genetic mutations within or near the βA4 domain, inappropriate production of AβPP isoforms, increased AβPP synthesis, or alterations in AβPP trafficking seem to favor this “amyloidogenic” cleavage, which is due to β-secretase activity. A major determining event in the production of βA4 amyloidogenic species appears to be the COOH-terminal cleavage, due to γ-secretase activity. This generates species either of 39/40 residues or longer species of 42/43/44 residues which have a greater tendency to aggregate. A central focus of current research is to elucidate the cellular trafficking and targeting of AβPP in order to understand how the various proteolytic systems operate and are selected. This could lead to the development of therapeutic agents which control the formation, aggregation or mobilization of cerebral amyloid in Alzheimer's disease.Keywords
This publication has 77 references indexed in Scilit:
- Characterization of proteases with the specificity to cleave at the secretase-site of β-APPNeuroscience Letters, 1993
- Modulation of β-Amyloid Precursor Protein Secretion in Differentiated and Nondifferentiated CellsBiochemical and Biophysical Research Communications, 1993
- Activation of the Secretory Pathway Leads to a Decrease in the Intracellular Amyloidogenic Fragments Generated from the Amyloid Protein PrecursorBiochemical and Biophysical Research Communications, 1993
- Secretory processing of the Alzheimer amyloid βA4 protein precursor is increased by protein phosphorylationBiochemical and Biophysical Research Communications, 1992
- Human brain peptidase activity with the specificity to generate the N-terminus of the Alzheimer β-amyloid protein from its precursorBiochemical and Biophysical Research Communications, 1992
- Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cellsNeuroscience Letters, 1991
- Alzheimer's disease amyloid β-clipping enzyme (APP secretase): Identification, purification, and characterization of the enzymeBiochemical and Biophysical Research Communications, 1991
- Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's diseaseNature, 1991
- Amyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's DiseaseNew England Journal of Medicine, 1989
- Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid proteinBiochemical and Biophysical Research Communications, 1984