Blockade of the tumor necrosis factor-related apoptosis inducing ligand death receptor DR5 prevents β-amyloid neurotoxicity

Daniela Uberti, Giulia Ferrari-Toninelli, Sara Anna Bonini, Ilenia Sarnico, Marina Benarese, Marina Pizzi, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, PierFranco Spano, Fabio Facchetti, Maurizio Memo

Research output: Contribution to journalArticlepeer-review

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 β peptide (Aβ) 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 β amyloid ranging from 10 nM to 1 μM, only the highest toxic dose of Aβ (25 μM) induced the increased expression of DR5 and neuronal cell death. In addition, the increased expression of DR5 receptor after β amyloid treatment was sustained by p53 transcriptional activity, as demonstrated by the data showing that the p53 inhibitor Pifithrin α prevented both β amyloid-induced DR5 induction and cell death. These data suggest a sequential activation of p53 and DR5 upon β 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.

Original languageEnglish
Pages (from-to)872-880
Number of pages9
JournalNeuropsychopharmacology
Volume32
Issue number4
DOIs
Publication statusPublished - Mar 7 2007

Keywords

  • β amyloid
  • Alzheimer's disease
  • Apoptosis
  • DR5 receptor
  • p53
  • TRAIL

ASJC Scopus subject areas

  • Pharmacology

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