Intracellular amyloid-β1-42, but not extracellular soluble amyloid-β 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 (Abeta), 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 A42/Abeta40 production. Abeta42 also accumulates in neurons of AD patients. Altogether, these data strongly suggest that the neuronal production of Abeta42 is a critical event in AD, but the intraneuronal Abeta42 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 Abeta1-40 and soluble APP, these extracellular derivatives do not induce neuronal death. On the contrary, neurons undergo apoptosis as soon as they accumulate intracellular Abeta1-42 following the expression of full-length APP or a C-terminal deleted APP isoform. The inhibition of intraneuronal Abeta1-42 production by a functional gamma-secretase inhibitor increases neuronal survival. Therefore, the accumulation of intraneuronal Abeta1-42 is the key event in the neurodegenerative process that we observed.