. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9(11):e111898. Epub 2014 Nov 12 PubMed.

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  1. Neurons contain multiple Aβ binding sites, from membrane receptors to gangliosides. It is currently unclear whether Aβ toxicity is mediated by ligand-receptor interactions or a less-specific mechanism. Using a phenotypic assay for membrane trafficking, Izzo et al. have identified low molecular weight compounds that blocked Aβ binding to neural membranes and displaced already-bound Aβ oligomers. Of note, Aβ-induced trafficking deficits were monitored by means of the MTT assay, whereby -treated cultures displayed enhanced exocytosis of the insoluble dye (formazan). While the MTT assay is unsuitable for evaluation of Aβ-induced cell death (Wogulis et al., 2005), it is a perfect tool for the study of Aβ effects on cell membrane.

    Using carefully characterized synthetic and human brain-derived Aβ aggregates, the authors demonstrate that an unprecedentedly high (more than 90 percent) level of oligomer binding is mediated by sigma-2/PGRMC1, a progesterone receptor membrane component 1 implicated in a few CNS disorders and cancer. Given the known role of sigma-2 in membrane trafficking and stabilization of transmembrane receptors, the authors raise an interesting possibility that Aβ interaction with this protein can modulate other candidate Aβ receptors as a part of a large multireceptor complex. Whether Aβ is an agonist or antagonist of sigma-2 is unclear, but caspase 3 activation, typical for sigma-2 agonists, does not seem to be involved in Aβ-induced synaptotoxic cascades. The affinity of sigma-2 for Aβ oligomers is relatively low (Kd = 0.5 μM), five to 10 times lower compared to other receptors (PrP, RAGE, and FcgR2B), and oligomers can be efficiently displaced from their binding sites by sigma-2 antagonists in a dose-dependent manner.

    This study is outstanding in three main aspects: compound-mediated displacement of bound oligomers has not been shown for other Aβ receptors; the neutralizing effect of sigma-2 allosteric antagonists holds for a remarkably broad array of Aβ species; and finally, the in vivo effects of sigma-2 antagonists on synapses and memory in two AD mouse models point to the therapeutic potential of these compounds.

    View all comments by Iryna Benilova

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