Isoprenoids and tau pathology in sporadic Alzheimer's disease

Neurobiol Aging. 2018 May;65:132-139. doi: 10.1016/j.neurobiolaging.2018.01.012. Epub 2018 Feb 2.

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.

Keywords: Alzheimer's disease; Farnesyl pyrophosphate synthase; Geranylgeranyl pyrophosphate synthase; Isoprenoids; Mevalonate pathway; Tau phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Cerebellum / metabolism*
  • Cerebellum / pathology*
  • Farnesyltranstransferase / physiology
  • Female
  • Frontal Lobe / metabolism*
  • Frontal Lobe / pathology*
  • Geranyltranstransferase / physiology
  • Humans
  • Male
  • Mevalonic Acid / metabolism
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Polyisoprenyl Phosphates / biosynthesis
  • Protein Prenylation
  • Sesquiterpenes
  • Terpenes / metabolism*
  • cdc42 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / metabolism
  • tau Proteins / metabolism*

Substances

  • Polyisoprenyl Phosphates
  • Sesquiterpenes
  • Terpenes
  • tau Proteins
  • farnesyl pyrophosphate
  • Geranyltranstransferase
  • Farnesyltranstransferase
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein
  • geranylgeranyl pyrophosphate
  • Mevalonic Acid

Grant support