Abeta 1–42 oligomer-induced trafficking deficits are prevented and competitively inhibited by sigma-2/PGRMC1 antagonists.

<p><b>A</b>, Reduced cargo dye (formazan) labels intracellular vesicles in vehicle-treated cultures, but is trafficked out of the cell more rapidly (<b>B</b>) following addition of synthetic Abeta oligomers (3 µM, total Abeta concentration). 15 µM CT0109 added 1 hr prior to Abeta restores trafficking to vehicle-treated levels (<b>C</b>) without affecting vesicles on its own (<b>D</b>). <b>E–H</b> Dose-response curves showing that CT0109 (<b>E</b>), CT0093 (<b>F</b>), CT01344 (<b>G</b>), and CT01346 (<b>H</b>) restore trafficking deficits whether added before (prevention) or after (treatment) addition of Abeta oligomers. <b>I–L</b>, synthetic Abeta oligomers exhibit a dose-dependent inhibition of membrane trafficking (red) that is right-shifted 5 to10-fold in the presence of increasing concentrations of sigma-2/PGRMC1 antagonists (<b>I</b>, CT0109: EC₅₀ = 0.5 µM to 5.3 µM; <b>J</b>, CT0093: EC₅₀ = 0.81 µM to 12.8 µM; <b>K</b>,CT01344: EC₅₀ = 1.7 µM to 7.1 µM; <b>L</b>, CT01346 EC₅₀ = 5.7 µM to 12.2 µM), consistent with pharmacological competition between compounds and Abeta oligomers. <b>M, N</b>, Abeta oligomers isolated from human postmortem AD patients exhibits a more potent dose-dependent inhibition of membrane trafficking (red), yet the same compounds inhibit the maximum effect of oligomers by 60 to 99% (P<0.025, t-test) making these oligomers less efficacious and therefore less toxic. <b>O</b>, CT0109 and CT0093 (0.2 µM, grey and black filled bars) reverse the trafficking deficit cause by human patient derived Abeta (1.5 pM, red bar) without affecting trafficking on their own (gray and black open bars).