## 3 Discussion
It is clear from these reports that phosphorylated Tau (p-Tau) protein level and NFT density in the frontal cortex resulted from increased FPP and GGPP synthesis, and that sterol regulatory element binding transcription factor 2 (_SREBF_2) gene expression levels in LOAD frontal cortices were inversely related to age of death. In contrast to immunoblotting, we could not demonstrate that the rise in A\(\beta\) concentration in medium collected from treatments came with the highest A\(\beta\) expression levels determined by Western blotting in cell lysates (Figure 3). Moreover, the A\(\beta\) concentration was lowest upon FOH or GGDH treatment, also in PC-12 cells expressing the Alzheimer relevant protein A\(\beta\)PP695 NL (\(A\beta\)PP-sw-bearing cells) (Figure 3E,F). The highest A\(\beta\) concentration was found in medium collected from MEV co-treatment (Figure 3B). This inconsistency could stem from A\(\beta\) intracellular preservation, which is common in different neuronal cell types examined [71; 72]. Immunocytochemistry combined with quantitative image analysis would be helpful to corroborate this hypothesis, since clear-cut revelation of intracellular A\(\beta\) is inadequate. It is worth noting that intracellular accumulation of A\(\beta\) precedes its extracellular export [73; 74; 75; 76] and causes synaptic pathology in AD associated with aberrant autophagy [40; 76; 77]. This study shows for the first time that CLU protein expression levels are inversely affected by statins which are inhibitors whereas non-sterol isoprenoids or water-soluble cholesterol are stimulatorsof this protein synthesis (Figure 4). Moreover, in empty-vector PC-12 neuronal cells (G) but not in those expressing sA\(\beta\)PP\(\alpha\) (W) or A\(\beta\) (S) the administration of GGGOH reduced CLU expression to control levels (Figure 4A). As CLU secretion is known to occur in inflammation, we suggest that GGGOH could repress the inflammatory response in A\(\beta\)PP expressing cells. This effect of GGGH is markedly reduced in _A\(\beta\)PP_-wt- and _A\(\beta\)PP_-sw-bearing cells. Therefore, expression of sA\(\beta\)PP\(\alpha\) (W) or A\(\beta\) (S) has a considerable impact on CLU protein expression levels. To shed the light on the neuroprotective role of GGGH/FOH in the survival of neuronal cells, it is tempting to follow reports from mevalonate kinase gene (_MVK_) deficiency (MKD). This is a rare enzymatic defect that is biochemically reproduced by the use of statins, the competitive HMGCR inhibitors. In a number of studies, it was demonstrated that MKD is associated with lower neuronal cell viability caused by inflammation, defective autophagy, oxidative stress, and programmed cell death [78; 79; 80]. Interestingly, cell death induced by the MEV pathway inhibitor lovastatin in SH-SYSY cells was hampered by GGGOH co-treatment [80], which is in agreement with our results, as the same isoprenoid restored viability reduced by ATR or SIM in PC-12 cells. Consequently, either MKD or statin-dependent blocking of the MEV pathway lead to oxidative stress, inflammatory response and apoptosis [81; 82; 83]. One possible scenario for apoptosis in MKD or statin-dependent blocking of the MEV pathway is defective autophagy, as autophagy which rescues cells from different insults is highly dependent on preynlated sGTPases [84; 85]. When autophagy is compromised via prenylation deficit of sGTPases, apoptosis takes over and cells undergo deletion. A body of evidence suggests that mitochondria are targeted by MKD or statins and that mitochondrial dysfunction is linked to apoptosis [79; 80; 86]. In addition, these spoiled mitochondria are not efficiently targeted for degradation in statin-treated cells showing autophagy (mitophagy) impairment followed by oxidative stress, apoptosis, DNA damage and cellular stress [78; 87]. Currently, we are undertaking an ongoing study centered on mitochondria, as these organelle exhibit drops in mitochondrial membrane potential (MMP) to statin treatment which is reversed by GGGH co-treatment [88].