Treatment of primary rat cortical neurons (DIV21) with various sigma 2 ligands reduces the uptake of Aβ42 monomers and oligomers in the presence and absence of apoE. Primary neurons were treated with 500nM RHM-4, SW43, or AG-205 and uptake of Aβ42 monomers, oligomers, and fibrils with or without apoE2, apoE3 or apoE4 was quantified. Uptake was compared to no compound treated controls (NT). Drug treatment resulted in a reduction of Aβ42 (A) monomers and (B) oligomers but not (C) fibrils when treated alone or in a complex with any apoE isoforms. (D-F) Quantification of apoE was assessed for these treatment groups. Cell associated Aβ42 and apoE was determined via ELISA of cell lysates normalized to total cell protein. Data represents mean ± SD (n=4); *, p < 0.05; **, p < 0.01; ***, p < 0.001; **** p < 0.0001; two way ANOVA for each treatment compared to control.