Intracellular amyloid-beta 1-42, but not extracellular soluble amyloid-beta peptides, induces neuronal apoptosis.
Alzheimer disease (AD), the most frequent cause of dementia, is characterized by an important neuronal loss. A typical histological hallmark of AD is the extracellular deposition of beta-amyloid peptide (A beta), which is produced by the cleavage of the amyloid precursor protein (APP). Most of the gene mutations that segregate with the inherited forms of AD result in increasing the ratio of A beta 42/A beta 40 production. A beta 42 also accumulates in neurons of AD patients. Altogether, these data strongly suggest that the neuronal production of A beta 42 is a critical event in AD, but the intraneuronal A beta 42 toxicity has never been demonstrated. Here, we report that the long term expression of human APP in rat cortical neurons induces apoptosis. Although APP processing leads to production of extracellular A beta 1-40 and soluble APP, these extracellular derivatives do not induce neuronal death. On the contrary, neurons undergo apoptosis as soon as they accumulate intracellular A beta 1-42 following the expression of full-length APP or a C-terminal deleted APP isoform. The inhibition of intraneuronal A beta 1-42 production by a functional gamma-secretase inhibitor increases neuronal survival. Therefore, the accumulation of intraneuronal A beta 1-42 is the key event in the neurodegenerative process that we observed.
Kienlen-Campard
Pascal
P
Université Catholique de Louvain, FARL/UCL 54 10, av Hippocrate 54, B-1200 Brussels, Belgium.
Miolet
Sarah
S
Tasiaux
Bernadette
B
Octave
Jean-Noël
JN
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016282:Aspartic Acid Endopeptidases; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017384:Sequence Deletion
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human