Selective Cytotoxicity of Intracellular Amyloid β Peptide1-42 through p53 and Bax in Cultured Primary Human Neurons

Extracellular amyloid β peptides (Aβs) have long been thought to be a primary cause of Alzheimer's disease (AD). Now, detection of intracellular neuronal Aβ 1-42 accumulation before extracellular Aβ deposits questions the relevance of intracellular peptides in AD. In the present study, we directly address whether intracellular Aβ is toxic to human neurons. Microinjections of Aβ 1-42 peptide or a cDNA-expressing cytosolic Aβ 1-42 rapidly induces cell death of primary human neurons. In contrast, Aβ 1-40, Aβ 40-1, or Aβ 42-1 peptides, and cDNAs expressing cytosolic Aβ 1-40 or secreted Aβ 1-42 and Aβ 1-40, are not toxic. As little as a 1-pM concentration or 1500 molecules/cell of Aβ 1-42 peptides is neurotoxic. The nonfibrillized and fibrillized Aβ 1-42 peptides are equally toxic. In contrast, Aβ 1-42 peptides are not toxic to human primary astrocytes, neuronal, and nonneuronal cell lines. Inhibition of de novo protein synthesis protects against Aβ 1-42 toxicity, indicating that programmed cell death is involved. Bcl-2, Bax-neutralizing antibodies, cDNA expression of a p53 R273 H dominant negative mutant, and caspase inhibitors prevent Aβ 1-42-mediated human neuronal cell death. Taken together, our data directly demonstrate that intracellular Aβ 1-42 is selectively cytotoxic to human neurons through the p53-Bax cell death pathway.