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

Zhang, Yan; McLaughlin, Richard; Goodyer, Cynthia; LeBlanc, Andréa

doi:10.1083/jcb.200110119

Cited by 418Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Zhang, Yan, McLaughlin, Richard, Goodyer, Cynthia, LeBlanc, Andréa·2002·The Journal of Cell Biology

DOI 10.1083/jcb.200110119PMC PMC2173346

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Abstract

Extracellular amyloid β peptides (Aβs) have long been thought to be a primary cause of Alzheimer's disease (AD). Now, detection of intracellular neuronal Aβ1–42 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 Aβ1–42 peptide or a cDNA-expressing cytosolic Aβ1–42 rapidly induces cell death of primary human neurons. In contrast, Aβ1–40, Aβ40–1, or Aβ42–1 peptides, and cDNAs expressing cytosolic Aβ1–40 or secreted Aβ1–42 and Aβ1–40, are not toxic. As little as a 1-pM concentration or 1500 molecules/cell of Aβ1–42 peptides is neurotoxic. The nonfibrillized and fibrillized Aβ1–42 peptides are equally toxic. In contrast, Aβ1–42 peptides are not toxic to human primary astrocytes, neuronal, and nonneuronal cell lines. Inhibition of de novo protein synthesis protects against Aβ1–42 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 Aβ1–42-mediated human neuronal cell death. Taken together, our data directly demonstrate that intracellular Aβ1–42 is selectively cytotoxic to human neurons through the p53–Bax cell death pathway.

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Intraneuronal Aβ42 accumulation in 5XFAD mice is either transient or obscured by plaque staining as mice age.
“suggesting that either intraneuronal Aβ42 accumulation is transient [27], or intracellular Aβ42 signal is obscured as plaque staining intensifies with age.”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [27]
The Introduction and Discussion say intracellular Aβ42 can appear before plaques, including in some transgenic mice, but neither says its accumulation is transient. Searches for transient accumulation and age-related plaque staining found no supporting passage. The citation is attached to the transient-accumulation possibility, not the separate suggestion that plaque staining obscures the signal; the paper does not discuss 5XFAD mice. (LLM, conf=0.76)
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Intraneuronal Aβ1-42 is particularly neurotoxic in vitro and in vivo.
“Intriguing in vitro and in vivo studies showed that intraneuronal Aβ1-42 was particularly neurotoxic [213]”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [213]

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Authors: Zhang, Y., McLaughlin, R., Goodyer, C., & LeBlanc, A.
Affiliations: Jewish General Hospital (CA)
3Neurochem, Inc., Ville Saint-Laurent, Québec H4S 2A1, Canada
McGill University (CA)
1Department of Neurology and Neurosurgery, McGill University, Montréal, Québec H3A 2T5, Canada
ORCID: Zhang, Yan
McLaughlin, Richard
Goodyer, Cynthia
Venue: The Journal of Cell Biology
Publisher: Rockefeller University Press
Published: 2002-01-28
Volume: 156
Issue: 3
Pages: 519-529
ISSN: 0021-9525 (ISSN-L)
1540-8140
DOI: 10.1083/jcb.200110119
PMC: PMC2173346
OpenAlex: W2007922488
Cited by: 418
References: 61
Citations by year: 2026: 2 · 2025: 11 · 2024: 13 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 8 · 2018: 11 · 2017: 9 · 2016: 8 · 2015: 15 · 2014: 21 · 2013: 23 · 2012: 18
FWCI: 19.98
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: cc-by-nc-sa
Locations: The Journal of Cell Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: intracellular amyloid-beta, amyloid-beta 42, neurotoxicity, neuronal cell death, p53, Bax, Alzheimer's disease, programmed cell death, caspases, Bcl-2, protein synthesis inhibition
MeSH terms: Alzheimer Disease, Astrocytes, Brain, Cells, Cultured, Enzyme Inhibitors, Fetus, Humans, Intracellular Fluid, Microscopy, Electron, Neurons, Peptide Fragments, Polymers, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Amyloid beta-Peptides, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Caspases, bcl-2-Associated X Protein, Plaque, Amyloid, Caspase Inhibitors

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

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