The expression of p75 neurotrophin receptor protects against the neurotoxicity of soluble oligomers of beta-amyloid.

In this paper, evidence is provided that p75 neurotrophin receptor (p75NTR) exerts an opposite role on the cytotoxic function of beta-amyloid (Abeta) depending on the different state of the peptide, fibrillar or oligomeric soluble form. Previous work in our laboratory has shown that the expression of p75NTR is required for cell death in vitro by Abeta peptides in fibrillar form (G. Perini, V. Della-Bianca, V. Politi, G. Della Valle, I. Dal-Pra, F. Rossi, U. Armato. Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J. Exp. Med. 195 (2002) 907-918). In the present study, performed by using the same cell clones and procedures as in previous paper, we show that: (a) soluble oligomers of Abeta(1-42) exert a cytotoxic activity independent of p75NTR, (b) the expression of p75NTR exerts a protective role against the toxic activity of soluble oligomers, (c) this role is due to an active function of the juxtamembrane sequence of the cytoplasmic region of p75NTR and (d) the protective function is mediated by phosphatidylinositide 3-kinase (PI3K) activity.