. The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J Neurosci. 2009 Aug 26;29(34):10627-37. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. Knowles et al. show that Aβ oligomers bind to the neurotrophin receptor p75 (cf. Costantini et al., 2005), that p75 substantially contributes to Aβ-induced neuronal death and neurite dystrophy, and that a significant part of the toxicity of Aβ oligomers is independent of wild-type p75 (cf. e.g., Costantini et al., 2005). Using Förster resonance energy transfer (FRET), they observed an unusually strong signal (50 percent reduction of donor emission) with donor FITC-Aβ and acceptor Cy3B-p75 that, in their interpretation, might be caused by the binding of multiple FITC-Aβ oligomers to p75; such binding could increase the probability of FRET occurrence or cause self-quenching of fluorescein and thus enlarge the apparent FRET signal. The FRET results, and their interpretation, would be consistent with the presence of a second binding site of Aβ on the p75 stalk close to the transmembrane domain—a binding site indicated by evidence presented in the Aβ-crosslinker hypothesis (see Current Hypotheses or www.abeta-p75.de).

    The binding of FITC-Aβ oligomers to both binding sites of Aβ on p75 could augment total energy transfer from FITC-Aβ to Cy3B-p75 or induce self-quenching of fluorescein and thereby diminish FITC emission and energy transfer to Cy3B-p75. With reverse fluorescence labeling (Cy3B-Aβ and FITC-p75), FITC should be located within the upper half of extracellular human p75 (containing the N-terminus and all extracellular, FITC-binding lysines), and Cy3B-Aβ bound to the neurotrophin binding site might shield stalk-bound Cy3B-Aβ against energy transfer from p75-bound FITC, which should result in a weaker FRET signal (20 percent in the study).

    The role of p75 in Aβ-induced neuronal degeneration described by Knowles et al. (and other researchers) contrasts with a neuroprotective effect of p75 against Aβ toxicity reported by Zhang et al. (2003), Costantini et al. (2005), and Bengoechea et al. (2009). The apparent conflict might be solved by the hypothesis that p75 can form neurotrophic and neuroprotective cooperation with APP, PrPc, and other proteins via stalk-bound Aβ oligomers. High concentrations of administered Aβ oligomers or excessive endogenous Aβ, however, should soon produce β-sheet Aβ, and the neuroprotective effect of p75 breaks down when β-sheet Aβ (instead of Aβ monomers and oligomers) binds to the p75 stalk, prevents the neuroprotective cooperation of p75, and dimerizes and activates the receptor. In this view, Aβ-stimulated p75 would protect neurons against Aβ toxicity as long as the Aβ load is not too high and substantial neuroprotective cooperation of p75 occurs, whereas continual stimulation of p75 with Aβ species and the prevention of neuroprotective cooperation of p75 by β-sheet Aβ would contribute to deleterious effects of Aβ.

    References:

    . p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2009 May 12;106(19):7870-5. PubMed.

    . The expression of p75 neurotrophin receptor protects against the neurotoxicity of soluble oligomers of beta-amyloid. Exp Cell Res. 2005 Nov 15;311(1):126-34. PubMed.

    . p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity. J Neurosci. 2003 Aug 13;23(19):7385-94. PubMed.

This paper appears in the following:

News

  1. Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs?