title: beta-Secretase cleavage of the amyloid precursor protein mediates neuronal apoptosis caused by familial Alzheimer's disease mutations.
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.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: McPhie
authors.forename: T
authors.initials: T
authors.lastname: Golde
authors.forename: C B
authors.initials: CB
authors.lastname: Eckman
authors.forename: D
authors.initials: D
authors.lastname: Yager
authors.forename: J B
authors.initials: JB
authors.lastname: Brant
authors.forename: R L
authors.initials: RL
authors.lastname: Neve
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D017077:Culture Media, Conditioned; D010450:Endopeptidases / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008131:London; D016254:Mutagenesis, Insertional; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism; D017354:Point Mutation; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D013548:Sweden; D019076:Transgenes
chemical_list: D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C509281:Bace1 protein, rat