engleski

Dopamine beta-hydroxylase and inflammatory cytokines in Alzheimer’s disease

Introduction: Alzheimer's disease (AD) is a complex and polygenetic neurodegenerative disease. It’s unclear etiology could be the result of interaction between genetic and environmental factors. Hallmarks of the disease are accumulation of senile plaques and neurofibrillary tangles. The loss of cholinergic neurons appears in the early stage of AD, while the degeneration of noradrenergic neurons occurs during the progression of disease. Noradrenalin is a neurotransmitter with possible neuroprotective and anti-inflammatory role throughout its effect on the expression of inflammatory mediators. Dopamine beta-hydroxylase (DBH) being a key enzyme in the synthesis of noradrenalin could modulate its neuroprotective role. Neuroinflammation also plays an important role in the development of AD. The aim of the present study was to determine plasma DBH activity and DBH (rs1611115, rs6271), inflammatory cytokines IL-1a (rs1800587), IL-1b (rs1143623), IL- 6 (rs1800795), IL-10 (rs1800896) and TNF-a (rs1800629) gene polymorphisms in patients with AD and elderly healthy controls. Those genetic variants were suspected high risk alleles which were also functional polymorphisms controling the expresson of particular cytokine. We determined also the ApoE (rs7412, rs429358) gene polymorphisms since it is so far the only probable marker for AD. Materials and Methods: The study included 207 patients with AD and 90 age and sex matched healthy controls. Plasma DBH activity was determined by a photometric method by Nagatsu and Udenfriend and gene polymorphisms using TaqMan Real-time allelic discrimination technique after extraction of DNA from whole blood with salting out procedure. Results: A decrease in plasma DBH activity was found in AD patients compared to controls or between AD patients in different stages of the disease. The changes in DBH activity were independent of the genetic variants in DBH gene. A significant difference was found in allele frequencies of the IL-10 gene between AD and controls, with higher frequency of the T allele as a “high risk” allele which is correlated to lower IL-10 expression in AD. There was no relationship between genetic variants of the other cytokines and AD. The results showed a higher frequency of carriers with E4 allele of the ApoE gene among patients with AD. The higher frequency of carriers with simultaneously E4 allele in ApoE gene and T allele in IL-10 gene was found in patients with AD than in controls, which showed clear synergistic effect of tested alleles. Conclusions: Decreased activity of DBH suggests lower noradrenalin synthesis and its diminished protective role in the development and progress of AD. The results propose that the synergistic effect between genetic variants in anti-inflammatory cytokine IL-10 and ApoE genes could be the marker for higher risk of AD development.

plasma DBH activity; DBH (rs1611115; rs6271); inflammatory cytokines IL-1a (rs1800587); IL-1b (rs1143623); IL-6 (rs1800795); IL-10 (rs1800896); TNF-a (rs1800629); Alzheimer's disease

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