engleski

Molecular basis of Alzheimer’s disease: association of dopamine-beta-hydroxylase and inflammatory cytokines

Aim: Alzheimer's disease (AD) is a multifactorial and polygenetic neurodegenerative disease. Its etiology is unclear but could be the result of interaction between genetic and environmental factors. The early stage of AD is related to the degeneration of cholinergic neurons, while the alterations in noradrenergic neurons occur with the progression of disease. Noradrenalin is a neurotransmitter with possible neuroprotective 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 is also an important factor in the etiology of AD, related to onset and progression of disease. The aim of the present study was to determine plasma DBH activity and DBH, inflammatory cytokines (IL-1a, IL-1b, IL-6, IL-10, TNF- a) and ApoE gene polymorphisms in patients with AD and elderly healthy controls. Methods: The study included 207 patients with AD and 90 healthy controls. Plasma DBH activity was determined by a photometric method 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 that 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 with lower IL-10 expression (“risk” allele) in AD. There was no relationship between genetic variants of 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. 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 markers for higher risk of AD development.

Alzheimer's disease; DBH activity; gene; nterleukin1; interleukin 6; interleukin 10; ApoE4; gene polymorphism

Indexed / Abstracted in: Neuroscience Citation Index ; EMBASE / Excerpta Medica