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A correction to this article has been published: J. Exp. Med. 195 (9) 1231
Published 1 April 2002. doi:10.1084/jem.20011797
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© Rockefeller University Press, 0022-1007/2002/4/907/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 7, April 1, 2002 907-918

Original Article

Role of p75 Neurotrophin Receptor in the Neurotoxicity by ß-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines

Giovanni Perini1, Vittorina Della-Bianca2, Valeria Politi1, Giuliano Della Valle1, Ilaria Dal-Pra3, Filippo Rossi2 and Ubaldo Armato3

1 Department of Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy
2 Department of Pathology, General Pathology Unit
3 Department of Biomedical and Surgical Sciences, Histology and Embryology Unit, University of Verona, 37134 Verona, Italy

Address correspondence to Filippo Rossi, Dept. of Pathology, General Pathology Unit, University of Verona, Strada Le Grazie, 8, 37134, Verona, Italy. Phone: 39-045-8027121; Fax: 39-045-8027127; E-mail: filippo.rossi{at}univr.it

The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of ß-amyloid peptides (Aß), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75NTR) is responsible for neuronal damage by interacting with Aß. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75NTR, we could show that p75NTR is involved in the direct signaling of cell death by Aß via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Aß could act synergistically. In fact, TNF-{alpha} and IL-1ß, cytokines produced by Aß-activated microglia, could potentiate the neurotoxic action of Aß mediated by p75NTR signaling. Together, our results indicate that neurons expressing p75NTR, mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Aß in AD.

Key Words: p75NTR • cell death • human neuroblastoma cells • cytokines • Alzheimer's disease


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