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Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM. 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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University College London
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 Aβ-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.
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