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

2002 ◽  
Vol 156 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Yan Zhang ◽  
Richard McLaughlin ◽  
Cynthia Goodyer ◽  
Andréa LeBlanc

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.

2003 ◽  
Vol 372 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Mar PÉREZ ◽  
Ana I. ROJO ◽  
Francisco WANDOSELL ◽  
Javier DÍAZ-NIDO ◽  
Jesús AVILA

Prion diseases are characterized by neuronal cell death, glial proliferation and deposition of prion peptide aggregates. An abnormal misfolded isoform of the prion protein (PrP) is considered to be responsible for this neurodegeneration. The PrP 106–126, a synthetic peptide obtained from the amyloidogenic region of the PrP, constitutes a model system to study prion-induced neurodegeneration as it retains the ability to trigger cell death in neuronal cultures. In the present study, we show that the addition of this prion peptide to cultured neurons increases the activity of glycogen synthase kinase 3 (GSK-3), which is accompanied by the enhanced phosphorylation of some microtubule-associated proteins including tau and microtubule-associated protein 2. Prion peptide-treated neurons become progressively atrophic, and die ultimately. Both lithium and insulin, which inhibit GSK-3 activity, significantly decrease prion peptide-induced cell death both in primary neuronal cultures and in neuroblastoma cells. Finally, the overexpression of a dominant-negative mutant of GSK-3 in transfected neuroblastoma cells efficiently prevents prion peptide-induced cell death. These results are consistent with the view that the activation of GSK-3 is a crucial mediator of prion peptide-induced neurodegeneration.


2001 ◽  
Vol 134 (3) ◽  
pp. 673-681 ◽  
Author(s):  
Tatsurou Yagami ◽  
Keiichi Ueda ◽  
Kenji Asakura ◽  
Toshiyuki Sakaeda ◽  
Takayuki Kuroda ◽  
...  

2002 ◽  
Vol 948 (1-2) ◽  
pp. 72-81 ◽  
Author(s):  
Tatsurou Yagami ◽  
Keiichi Ueda ◽  
Kenji Asakura ◽  
Takayuki Kuroda ◽  
Satoshi Hata ◽  
...  

2013 ◽  
Vol 34 (1) ◽  
pp. 226-237 ◽  
Author(s):  
Gayle H. Doherty ◽  
Dayne Beccano-Kelly ◽  
Shi Du Yan ◽  
Frank J. Gunn-Moore ◽  
Jenni Harvey

2014 ◽  
Vol 61 ◽  
pp. 46-55 ◽  
Author(s):  
Ryan T. Cameron ◽  
Steven D. Quinn ◽  
Lynn S. Cairns ◽  
Ruth MacLeod ◽  
Ifor D.W. Samuel ◽  
...  

2009 ◽  
Vol 108 (5) ◽  
pp. 1116-1125 ◽  
Author(s):  
Min-Young Noh ◽  
Seong-Ho Koh ◽  
Youngchul Kim ◽  
Hyun Young Kim ◽  
Goang Won Cho ◽  
...  

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