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Published online 28 January 2002. doi:10.1083/jcb.200110119
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© The Rockefeller University Press, 0021-9525/2002/2/519 $5.00
The Journal of Cell Biology, Volume 156, Number 3, February 4, 2002 519-529

Article

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

Yan Zhang1,4, Richard McLaughlin3, Cynthia Goodyer2 and Andréa LeBlanc1,4

1 Department of Neurology and Neurosurgery, McGill University, Montréal, Québec H3A 2T5, Canada
2 Department of Pediatrics, McGill University, Montréal, Québec H3A 2T5, Canada
3 Neurochem, Inc., Ville Saint-Laurent, Québec H4S 2A1, Canada
4 The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec H3T 1E2, Canada

Address correspondence to Andréa LeBlanc, The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte Ste-Catherine Rd., Montréal, Québec H3T 1E2, Canada. Tel.: (514) 340-8260 Fax: (514) 340-8295. E-mail: andrea.leblanc{at}mcgill.ca

Extracellular amyloid ß peptides (Aßs) have long been thought to be a primary cause of Alzheimer's disease (AD). Now, detection of intracellular neuronal Aß1–42 accumulation before extracellular Aß deposits questions the relevance of intracellular peptides in AD. In the present study, we directly address whether intracellular Aß is toxic to human neurons. Microinjections of Aß1–42 peptide or a cDNA-expressing cytosolic Aß1–42 rapidly induces cell death of primary human neurons. In contrast, Aß1–40, Aß40–1, or Aß42–1 peptides, and cDNAs expressing cytosolic Aß1–40 or secreted Aß1–42 and Aß1–40, are not toxic. As little as a 1-pM concentration or 1500 molecules/cell of Aß1–42 peptides is neurotoxic. The nonfibrillized and fibrillized Aß1–42 peptides are equally toxic. In contrast, Aß1–42 peptides are not toxic to human primary astrocytes, neuronal, and nonneuronal cell lines. Inhibition of de novo protein synthesis protects against Aß1–42 toxicity, indicating that programmed cell death is involved. Bcl-2, Bax-neutralizing antibodies, cDNA expression of a p53R273H dominant negative mutant, and caspase inhibitors prevent Aß1–42-mediated human neuronal cell death. Taken together, our data directly demonstrate that intracellular Aß1–42 is selectively cytotoxic to human neurons through the p53–Bax cell death pathway.

Key Words: Alzheimer's disease; amylois ß peptide; p53; Bax; neurotoxicity


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