P2‐124: Brain Isoprenoids and Alzheimer's Disease
Bibliographic record
Abstract
The mevalonate pathway has been described to play a key role in Alzheimer's disease (AD). Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are non-sterol isoprenoid intermediates from mevalonate. They lead to protein prenylation which plays a crucial role in controlling cell signalling and proliferation. hFPP and hGGPP synthases lead to prenylation of small GTPase protein RhoA-cdc42, that have been shown to be associated with the accumulation of phospho-tau protein in the brain. It is hypothesise that these intermediates are implicated in tau dysregulation and the progression of 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. In the first part of this work, we measured cortical mRNA levels of hFPPs and hGGPPs (RT-qPCR) and, GGPP and FPP concentrations by Liquid chromatography-tandem mass spectrometry (LC/MS/MS) in control and AD brain tissues obtained from the Douglas-Bell Brain Bank (Montréal, Canada). In the second part, hFPPs and hGGPPs inhibitors derived from the nitrogen-containing bisphosphonates (N-BP) were tested on human SH-SY5Y neurons and their effect on the accumulation of tau and Phospho-tau was measured as a function of time and concentrations. In autopsied frontal cortex, we found a significant positive correlation between mRNA levels (p<0.001, n=124), FFP and GGPP (p<0.05, n=116) and disease status. The levels of mRNA for hFFPs and hGGPPs also correlated with the amount of phospho-tau protein levels (p<0.05, n=38) and neurofibrillary tangles density (p<0.006, n=40) in frontal cortex. We also found that high levels of hFPPS and hGGPPS mRNA prevalence is significantly associated with earlier age of onset in AD (p<0.05, n=64). Finally, preliminary data indicates that our novel families of inhibitors can decrease phospho-tau levels in SH-SY5Y neurons without any detectable toxicity. Together, these results suggest that accumulation of phospho-tau in the AD brain is related to increase levels of neuronal isoprenoids; a phenomenon that could be alleviated by the administration of specific and potent bi-phosphonate derivatives. supported by the J.L. Lévesques Foundation, Canadian Institute of Health Research and FQRNT.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".