Selective cytotoxicity of intracellular amyloid β peptide1-42 through p53 and Bax in cultured primary human neurons

Extracellular amyloid beta peptides (Abetas) have long been thought to be a primary cause of Alzheimer's disease (AD). Now, detection of intracellular neuronal Abeta(1-42) accumulation before extracellular Abeta deposits questions the relevance of intracellular peptides in AD. In the present study, we directly address whether intracellular Abeta is toxic to human neurons. Microinjections of Abeta(1-42) peptide or a cDNA-expressing cytosolic Abeta(1-42) rapidly induces cell death of primary human neurons. In contrast, Abeta(1-40), Abeta(40-1), or Abeta(42-1) peptides, and cDNAs expressing cytosolic Abeta(1-40) or secreted Abeta(1-42) and Abeta(1-40), are not toxic. As little as a 1-pM concentration or 1500 molecules/cell of Abeta(1-12) peptides is neurotoxic. The nonfibrillized and fibrillized Abeta(1-42) peptides are equally toxic. in contrast, Abeta(1-42) peptides are not toxic to human primary astrocytes, neuronal, and nonneuronal cell lines. Inhibition of de novo protein synthesis protects against Abeta(1-42) toxicity, indicating that programmed cell death is involved. Bcl-2, Bax-neutralizing antibodies, cDNA expression of a p53(R273H) dominant negative mutant, and caspase inhibitors prevent Abeta(1-42)-mediated human neuronal cell death. Taken together, our data directly demonstrate that intracellular Abeta(1-42) is selectively cytotoxic to human neurons through the p53-Bax cell death pathway.