ISOPRENOIDS PATHWAY, TAU PHOSPHORYLATION AND ALZHEIMER’S DISEASE

The mevalonate pathway has been shown to play a central role in Alzheimer's disease (AD) physiopathology via modulation of the amyloid and tau metabolisms. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are non-sterol isoprenoid intermediates from mevalonate and, are precursor to numerous metabolites in the CNS. They are involved in protein prenylation which regulates cell signalling, differentiation and proliferation. hFPP and hGGPP synthases serve as gateway enzymes to the prenylation of the small GTPase protein RhoA-cdc42; a protein associated with the accumulation of phospho-Tau protein in neurons of the brain. It has been hypothesised that these some of the key intermediates are implicated in tau dysregulation and phosphorylation and the accumulation of tangles in AD. A better understanding of the role of hFPPS and hGGPPS in the pathophysiology of Alzheimer's disease may prove to be essential to assess the function of the isoprenoids pathway as a potential target in prevention of AD. Cortical mRNA prevalence of hFPPS and hGGPPS enzymes was assessed by qRT-PCR whereas, GGPP, FPP and cholesterol levels were measured using Liquid chromatography-tandem mass spectrometry (LC/MS/MS) in autopsied AD and age-matched control brain tissues obtained from the Douglas-Bell Brain Bank (Montréal, Canada). A significant positive correlation was found between mRNA levels (p<0.001, n=124), FFP and GGPP (p<0.05, n=116) and disease status. mRNA prevalence for hFFPs and hGGPPs positively correlates with phospho-tau protein levels (p<0.05, n=38, Fujirebio ELISA kit) and neurofibrillary tangles density (p<0.006, n=40) in cortical areas. Furthermore, high tissues levels of hFPPS and hGGPPS in cortical areas significantly correlates with earlier age of onset in AD cases (p<0.05). Finally, cortical mRNA prevalence of hFPPS and hGGPPS positively correlate with HMGCoA- reductase proteins levels but not with tissues cholesterol levels; consistent with the proposed cholesterol-independent isoprenoid-dependent cascade hypothesis. Together, these results suggest that accumulation of phospho-tau in the AD brain is mediated, at least in part, by local increases in neuronal isoprenoids; a phenomenon that could be alleviated by the administration of specific and potent bi-phosphonate derivatives.