## 2 Results
Full reversal of ATR-, and to some extent SIM- or M\(\beta\)CD-induced cytotoxicity was observed in PC-12 neuronal cells with \(A\beta\)PP-wt, \(A\beta\)PP-sw or empty vector after administration of 10 uM GGGH (Figure 2F). The cytoprotective effect of GGGH against ATR-induced cytotoxicity was significant, or highly significant in comparison to SIM- or M\(\beta\)CD-treated cells (Figure 2F). Astonishingly, no other non-sterol isoprenoid, except FOH, mimicked GGGH in reversal any statin- or M\(\beta\)CD-dependent loss in cell viability although some co-treatments (MEV, DOH, UBOH) led to statistically significant differences in average viability between \(A\beta\)PP-wt, (W), and \(A\beta\)PP-sw, (S) transfected cells (Figure 2B-2E). FOH, similarly to GGGH, reversed ATR- and M\(\beta\)CD-toxicity of \(A\beta\)PP-sw cells to control levels (Figure 2E, \(p>0.05\)). Figure 1A and 2A are the same for clearer demonstration of differences in cell viability between statins or M\(\beta\)CD given alone or co-treated with soluble cholesterol vs. MEV pathway intermediates. Figure 2: Cont. Effects of Selected MEV Pathway Enzyme Inhibitors on Cell Viability of Neuronal PC-12 Cells Overexpressing Wild-Type and Mutated (Swedish Mutation) A\(\beta\)PP Gene  
To gain insight into the cellular pathways translating into the reduced cell viability depicted in Figure 1, additional analysis with selected MEV pathway enzyme inhibitors was carried out. As illustrated in Supplementary data 3, zaragozic acid (squalene synthase inhibitor), L-744,832 (farnesyl transferase inhibitor), or GGTI-286 (geranylgeranyl transferase I inhibitor) dose-dependently reduced cell viability similarly to statins or M\(\beta\)CD. These observations confirm the importance of the inhibited steps in MEV pathway for neuronal cell survival regardless of transfected gene. Next, we sought which intermediate of MEV pathway is essential for viable cell population impeded by statins or M\(\beta\)CD. Figure 2: Effect of mevalonate (MEV, 100 \(\upmu\)M), dolichol (DOH, 0.1 \(\upmu\)g/mL), ubiquinol (UBOH, 10 \(\upmu\)g/mL), farnesol (FOH, 10 \(\upmu\)M) or geranylgeraniol (GGOH, 10 \(\upmu\)M) on cell viability affected by MEV pathway modulators (atorvastatin – ATR, simvastatin – SIM, 50 \(\upmu\)M each) or cholesterol chelator methyl-ß-cyclodextrintrin (M\(\beta\)CD, 0.2 mM). One day (24 h) treatment with (**A**) ATR or SIM (50 \(\upmu\)M) or M\(\beta\)CD (0.2 mM) alone or (**B**) together with MEV, (**C**) or with DOH, (**D**) or with UBOH. Bar charts show percentage (% control) cell viability measured by MTT assay. Two-way ANOVA test followed by [PERSON]’s multiple comparisons were employed to analyze the data. (**A**) ATR, SIM or M\(\beta\)CD dose-dependently diminished fraction of viable cells. Except M\(\beta\)CD, neither \(A\beta\)PP-wt, nor Swedish mutation \(A\beta\)PP-sw gene affected ATR- or SIM-dependent effects on viable cells in comparison to empty-vector transfected cells. The results amounted to: \(p<0.0302\) for interaction, \(p<0.1409\) for genes, \(p<0.0001\) for ATR; \(p<0.0629\) for interaction, \(p<0.338\) for genes, \(p<0.0001\) for SIM; \(p<0.0343\) for interaction, \(p<0.0024\) for genes, \(p<0.0667\) for M\(\beta\)CD. (**B**) Adding MEV could rescue ATR, or SIM, or M\(\beta\)CD diminished viable cells. Both \(A\beta\)PP-wt and Swedish mutation \(A\beta\)PP-sw genes affected MEV-dependent effects on viable cells in comparison to empty-vector transfected cells. The results amounted to: \(p<0.016\) for interaction, \(p<0.0112\) for genes, \(p<0.0001\) for MEV. (**C**) Adding DOH rescued ATR, or SIM, or M\(\beta\)CD diminished viable cells. Neither \(A\beta\)PP-wt, nor Swedish mutation \(A\beta\)PP-sw gene affected DOH-dependent effects on viable cells in comparison to empty-vector transfected cells. The results amounted to: \(p<0.0153\) for interaction, \(p<0.04076\) for genes, \(p<0.0001\) for DOH. (**D**) Adding UBOH rescued ATR, or SIM, or M\(\beta\)CD diminished viable cells.