## 3 Discussion
Previously [36], and here, we have demonstrated that A\(\beta\)PP processing is determined by the presence of an additional _A\(\beta\)PP_ gene. A\(\beta\)PP C-terminal fragment (sA\(\beta\)PP\(\alpha\)) stems from A\(\beta\)PP in the _A\(\beta\)PP_-wt-bearing cells, but could be found neither in empty-vector or cellshaving the \(A\beta\)PP-sw gene (Figure 4A,B). Contradictory to empty-vector and \(A\beta\)PP-wt-bearing cells, the A\(\beta\) peptide was expressed solely in \(A\beta\)PP-sw-bearing cells (Figure 4A,B). Overall it points to distinct mechanisms of A\(\beta\)PP processing in empty-vector, \(A\beta\)PP-wt-, and \(A\beta\)PP-sw-bearing cells. In addition, the expression of A\(\beta\)PP C-terminal fragment sA\(\beta\)PP\(\alpha\) was markedly elevated in ATR- or SIM-treated \(A\beta\)PP-wt-bearing cells, while its expression was reduced by co-treatment with isoprenoids or Chol-PEG. Effects of isoprenoids given separately were similar with respect to A\(\beta\) expression levels compared to co-treatment with ATR or SIM in \(A\beta\)PP-sw-bearing cells (Figure 4A,B). ATR but not SIM administration inhibited A\(\beta\) expression (Figure 4A,B). Chol-PEG was incapable of reversing the ATR effect, which substantiates the idea that isoprenoids somehow control A\(\beta\)PP processing to A\(\beta\). Isoprenylation of some sGTPases seems to be involved in AD, as Rab-6 GTPase levels are augmented in affected individuals and control presenilin 1, which in turn assists \(\gamma\)-secretase in A\(\beta\) formation [58; 59]. Complementary to our findings, endogenous isoprenoids FPP and GGPP given to H4 neuroglioma cells expressing \(A\beta\)PP-sw gene increased A\(\beta\) production imitating AD, although different forms (pyrophosphates) and/or higher concentrations of isoprenoids were used by authors [60]. Our observations suggest that homeostasis of non-sterol isoprenoids is of higher importance than cholesterol itself in \(A\beta\)PP-sw-bearing cells. These data differ from reports of some authors [56; 57; 61], but are in agreement with others [3; 60; 62]. It is worth noting that amplifying the MEV pathway is cytoprotective via upstream famresyl transferase (F\(\overline{\text{F}}\)ase) and/or geranyl transferas (GGTases), rather than squalene synthase (SQS) once GGTase I is fully operational, which was demonstrated in skeletal muscle cells [47]. What comes up to the sight is that enzyme activity of the MEV pathway should be met by substrate delivery, since inhibition of GGTase I resulted in GGDH cytotoxic side-effects [47]. Thus, the balance between MEV pathway activity and substrate fluxes has a fundamental connotation, as a brain with elevated GGPP exhibited lower mRNA and GGTase I activity [51]. This idea is substantiated by the elevated concentrations of FPP and GGPP determined in post-mortem AD brains compared to healthy brains [63]. Previously, similar findings were reported for dolichol and ubiquinone levels, which rose in elderly and AD brains [64; 65; 66]. If, as some authors claim, statins could be regarded as drugs for AD [57; 63], it raises concern that inhibition of HMG affects the isoprenoids more than cholesterol. There is no clear evidence that statins exhibit any beneficial effect on amyloid plaque density at autopsy, although use of statins by healthy elderly individuals correlated with significant reduction of Tau protein in cerebrospinal fluid (CSF) [67] and brain neurofibrillary tangles (NFT) density compared to statin nonusers [68]. Accordingly, the aberrant protein prenylation has a greater effect on AD than cholesterol itself [62]. Most recent experiments bring to light cholesterol metabolism in pathology of sporadic AD (late-onset Alzheimer's disease, LOAD), as well as genes related to sterol metabolism [69; 70].