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Isoprenoids and tau pathology in sporadic Alzheimer's disease
Sandra Pelleieux1, Cynthia Picard2, Louise Lamarre-Théroux1
1Douglas Mental Health University Institute, McGill University, Montreal, Canada.
Abstract:
The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD) physiopathology. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are nonsterol isoprenoids derived from mevalonate, which serve as precursors to numerous human metabolites. They facilitate protein prenylation; hFPP and hGGPP synthases act as gateway enzymes to the prenylation of the small guanosine triphosphate (GTP)ase proteins such as RhoA and cdc42 that have been shown to facilitate phospho-tau (p-Tau, i.e., protein tau phosphorylated) production in the brain. In this study, a significant positive correlation was observed between the synthases mRNA prevalence and disease status (FPPS, p < 0.001, n = 123; GGPPS, p < 0.001, n = 122). The levels of mRNA for hFPPS and hGGPPS were found to significantly correlate with the amount of p-Tau protein levels (p < 0.05, n = 34) and neurofibrillary tangle density (p < 0.05, n = 39) in the frontal cortex. Interestingly, high levels of hFPPS and hGGPPS mRNA prevalence are associated with earlier age of onset in AD (p < 0.05, n = 58). Together, these results suggest that accumulation of p-Tau in the AD brain is related, at least in part, to increased levels of neuronal isoprenoids.
Insights
Increased levels of neuronal isoprenoids, specifically farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) synthases, correlate with Alzheimer's disease (AD) progression and phospho-tau (p-Tau) accumulation in the brain.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- The mevalonate pathway produces nonsterol isoprenoids like FPP and GGPP, crucial for protein prenylation.
- These isoprenoids are precursors to metabolites involved in cellular processes.
- Protein prenylation by hFPP and hGGPPS synthases influences small GTPase activity, linked to phospho-tau (p-Tau) production.
Purpose of the Study:
- To investigate the correlation between mevalonate pathway enzymes and Alzheimer's disease (AD) pathology.
- To determine the relationship between FPP and GGPP synthase mRNA levels and p-Tau accumulation.
- To explore the association of these synthases with AD onset age and neurofibrillary tangle density.
Main Methods:
- Quantification of hFPPS and hGGPPS mRNA prevalence in human brain samples.
- Correlation analysis between synthase mRNA levels and AD disease status.
- Statistical analysis of mRNA levels against p-Tau protein levels and neurofibrillary tangle density.
- Examination of the association between synthase mRNA levels and age of AD onset.
Main Results:
- Significant positive correlation found between FPPS and GGPPS mRNA levels and AD disease status (p < 0.001).
- hFPPS and hGGPPS mRNA levels significantly correlated with p-Tau protein levels (p < 0.05) and neurofibrillary tangle density (p < 0.05).
- Higher hFPPS and hGGPPS mRNA prevalence was associated with an earlier age of onset in AD patients (p < 0.05).
Conclusions:
- Increased neuronal isoprenoid levels, mediated by hFPPS and hGGPPS, are linked to p-Tau accumulation in the AD brain.
- The mevalonate pathway and its products represent a potential therapeutic target for Alzheimer's disease.
- These findings highlight the role of isoprenoid metabolism in the molecular mechanisms underlying AD pathogenesis.