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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 (p75^NTR) 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 p75^NTR, we could show that p75^NTR 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- and IL-1ß, cytokines produced by Aß-activated microglia, could potentiate the neurotoxic action of Aß mediated by p75^NTR signaling. Together, our results indicate that neurons expressing p75^NTR, mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Aß in AD.

Key Words: p75^NTR • cell death • human neuroblastoma cells • cytokines • Alzheimer's disease

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