Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline

Abstract

Mitochondrial bioenergetics, mitochondrial reactive oxygen species (ROS) and cellular levels of nucleotides have been hypothesized as early indicators of Alzheimer’s disease (AD). Utilizing relative decline of cognitive ability as a predictor of AD risk, we evaluated the correlation between change of cognitive ability and mitochondrial bioenergetics, ROS and cellular levels of deoxyribonucleotides. Change of cognitive abilities, scored at ages of approximately 20 and 57 was determined for a cohort of 1985 male participants. Mitochondrial bioenergetics, mitochondrial ROS and whole-cell levels of deoxyribonucleotide triphosphates were measured in peripheral blood mononuclear cells (PBMCs) from a total of 103 selected participants displaying the most pronounced relative cognitive decline and relative cognitive improvement. We show that relative cognitive decline is associated with higher PBMC content of deoxythymidine-triphosphate (dTTP) (20%), but not mitochondrial bioenergetics parameters measured in this study or mitochondrial ROS. Levels of dTTP in PBMCs are indicators of relative cognitive change suggesting a role of deoxyribonucleotides in the etiology of AD.

The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

“…Furthermore, we postulate a dNTP based vicious cycle where imbalance of the cytosolic dNTP pool will induce mutation and depletion of mtDNA, which in turn will impact on the de novo synthesis of dNTP through decreased function of the DHODHase and decreased activation of the RNR due to lower levels of ATP. Our hypotheses are consistent with the suggestion that altered abundance of cytosolic dNTPs may be an early marker of susceptibility to AD [85]…”

“…In eukaryotes, nucleotide levels are maintained by nucleotide salvage and/or de novo synthesis of ribo- and deoxyribonucleotide triphosphates (rNTPs and dNTPs). Imbalanced dNTP pools have been demonstrated in cells from AD individuals [84] and may be an early risk marker for AD [85]. Thus, it is possible that rNTP and/or dNTP pool imbalances play a role in the aetiology of AD, although the underlying mechanism remains unknown [85].…”

“…Imbalances of the dNTP levels have been correlated with risk of AD [84, 85]. These imbalance events can be symptomatic of AD which in itself is an important realization and a fact that hopefully can be used for early AD risk assessment in the near future [85].…”

“…Imbalances of the dNTP levels have been correlated with risk of AD [84, 85]. These imbalance events can be symptomatic of AD which in itself is an important realization and a fact that hopefully can be used for early AD risk assessment in the near future [85]. The mitochondrial relation to de novo synthesis of rNTP and dNTP, and in turn the strong impact of CTP in synthesis of essential phospholipids and the important role of de novo synthesized dNTP for maintenance of mtDNA, strongly indicates a causal role of mitochondrial impact on rNTP and dNTP synthesis in the aetiology of AD.…”

Simvastatin improves mitochondrial respiration in peripheral blood cells

“…The participants were fasted overnight and sampled the following morning. PBMCs were isolated as previously described 56 with minor changes, including a platelet purification step as described 57 . Platelets, and PBMCs were used immediately for extracellular flux assay, and mitochondrial superoxide measurement, or cryopreserved in freezing medium (70% FBS, 25% Roswell Park Memorial Institute (RPMI) 1640, (Thermo Fisher Scientific- Life tech.…”