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β-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer’s disease mutations
- Source :
- Molecular Brain Research. 97:103-113
- Publication Year :
- 2001
- Publisher :
- Elsevier BV, 2001.
-
Abstract
- The amyloid precursor protein (APP) is cleaved by two enzymes, beta-secretase and gamma-secretase, to generate the pathological amyloid beta (Abeta) peptide. Expression of familial Alzheimer's disease (FAD) mutants of APP in primary neurons causes both intracellular accumulation of the C-terminal beta-secretase cleavage product of APP and increased secretion of Abeta, and eventually results in apoptotic death of the cells. To determine whether either of these two processing products of APP is involved in this apoptotic pathway, we first modeled experimentally the accumulation of the beta-secretase cleavage product in neurons. The C-terminal 100 amino acids (C100) of APP, with and without a signal peptide, was expressed in cells via recombinant herpes simplex virus (HSV) vectors. Both transgene products were targeted to the membrane, and both caused apoptosis in the neurons, implicating the beta-secretase cleavage product of APP in apoptosis caused by FAD APPs. Expression in neurons of a mutant of FAD APP that inhibited beta-secretase cleavage inhibited its ability to cause apoptosis. However, expression in neurons of a mutant of FAD APP that inhibited gamma-secretase cleavage did not inhibit the ability of this mutant to cause apoptosis. These data suggested that the C-terminal beta-secretase cleavage product of APP, but not Abeta, mediates the apoptosis caused by FAD mutants of APP. Consistent with this hypothesis, C31, which is generated from the beta-secretase cleavage product, itself caused neuronal apoptosis. Inhibitors of caspases 3, 6 and 8, but not of caspase 9, inhibited the apoptosis caused by FAD mutants of APP. It may be inferred from these data that beta-secretase cleavage of FAD mutants of APP allows the appropriate caspase access to its site of action to produce C31, which directly causes neuronal apoptosis.
- Subjects :
- Amyloid beta
Genetic Vectors
Apoptosis
Nerve Tissue Proteins
Cleavage (embryo)
Amyloid beta-Protein Precursor
Cellular and Molecular Neuroscience
Alzheimer Disease
Endopeptidases
London
mental disorders
medicine
Amyloid precursor protein
Animals
Aspartic Acid Endopeptidases
Humans
Point Mutation
Simplexvirus
Transgenes
Molecular Biology
Caspase
Sweden
Caspase-9
biology
Neurodegeneration
medicine.disease
Peptide Fragments
Rats
Cell biology
Mutagenesis, Insertional
Amino Acid Substitution
Biochemistry
Caspases
Culture Media, Conditioned
Mutagenesis, Site-Directed
biology.protein
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
Subjects
Details
- ISSN :
- 0169328X
- Volume :
- 97
- Database :
- OpenAIRE
- Journal :
- Molecular Brain Research
- Accession number :
- edsair.doi.dedup.....995691d664d2627bc6b7eb0ef968475b