1. ¹Department of Biomedical Sciences and Biotechnologies, University of Brescia Medical School, Brescia, Italy
2. ²NeuroBioGen Lab-Memory Clinic, IRCCS 'Centro San Giovanni di Dio-FBF', Brescia, Italy
3. ³Department of Pathology, University of Brescia Medical School, Brescia, Italy

Correspondence: Dr D Uberti, Department of Biomedical Sciences and Biotechnologies, University of Brescia Medical School, Viale Europa 11, 25123 Brescia, Italy. Tel: +390303717509, Fax: +390303717529, E-mail: uberti@med.unibs.it

Received 21 March 2006; Revised 13 June 2006; Accepted 27 June 2006; Published online 16 August 2006.

Abstract

We originally suggested that inhibition of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) death pathway could be taken into consideration as a potential therapeutic strategy for Alzheimer's disease (AD). However, because the critical role of TRAIL in immune surveillance, the neutralization of TRAIL protein by an antibody to prevent its binding to death receptors is definitely a risky approach. Here, we demonstrated that the blockade of the TRAIL death receptor DR5 with a specific antibody completely prevented amyloid peptide (A) neurotoxicity in both neuronal cell line and primary cortical neurons. DR5 was demonstrated to be a key factor in TRAIL death pathway. In fact, whereas TRAIL expression was enhanced dose-dependently by concentrations of amyloid ranging from 10 nM to 1 M, only the highest toxic dose of A (25 M) induced the increased expression of DR5 and neuronal cell death. In addition, the increased expression of DR5 receptor after amyloid treatment was sustained by p53 transcriptional activity, as demonstrated by the data showing that the p53 inhibitor Pifithrin prevented both amyloid-induced DR5 induction and cell death. These data suggest a sequential activation of p53 and DR5 upon amyloid exposure. Further insight into the key role of DR5 in AD was suggested by data showing a significant increase of DR5 receptor in cortical slices of AD brain. Thus, these findings may give intracellular TRAIL pathway a role in AD pathophysiology, making DR5 receptor a possible candidate as a pharmacological target.