Genotype-independent decrease in plasma dopamine beta-hydroxylase activity in Alzheimer's disease

Abstract

The noradrenergic system is involved in the etiology and progression of Alzheimer’s disease (AD) but its role is still unclear. Dopamine beta-hydroxylase (DBH) as a catecholamine-synthesizing enzyme plays a central role in noradrenaline (NA) synthesis and turnover. Plasma DBH (pDBH) activity shows wide inheritable interindividual variability that is under genetic control. The aim of this study was to determine pDBH activity, DBH (C-970T; rs1611115) and DBH (C1603T; rs6271) gene polymorphisms in 207 patients with AD and in 90 healthy age-matched controls. Plasma DBH activity was lower, particularly in the early stage of AD, compared to values in middle and late stages of the disease, as well as to control values. Two-way ANOVA revealed significant effect of both diagnosis and DBH (C-970T) or DBH (C1603T) genotypes on pDBH activity, but without significant diagnosis×genotype interaction. No association was found between AD and DBH C-970T (OR=1.08, 95% CI 1.13–4.37; p=0.779) and C1603T (OR=0.89; 95% CI 0.36–2.20; p=0.814) genotypes controlled for age, gender, and ApoE4 allele. The decrease in pDBH activity, found in early phase of AD suggests that alterations in DBH activity represent a compensatory mechanism for the loss of noradrenergic neurons, and that treatment with selective NA reuptake inhibitors may be indicated in early stages of AD to compensate for loss of noradrenergic activity in the locus coeruleus.

Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer’s Disease, Parkinson’s Disease and Schizophrenia: Evidence Based on Currently Available Loci

“…Many genes, such as apolipoprotein E (APOE) [62], triggering receptor expressed on myeloid cells 2 (TREM2) [63], and methylene tetrahydrofolate reductase (MTHFR) [64], in combination with environmental factors result in a network of interplay in AD development. DBH catalyzes the oxidative hydroxylation of DA to NE, and recent evidence indicated that NE is not only a risk factor but also an actual etiological factor of AD [22]. We collected seven studies on the association of DBH polymorphisms at three loci (rs1611115, rs5320, and rs1611131) with the risk of AD.…”

“…Neuropathological analysis of PD indicates that the retrogression of dopaminergic neurons in the substantia nigra leads to a DA deficiency in the corpus striatum [3]. The DBH enzyme is an important member of the DA system, and evidence has shown that under certain conditions, DBH can influence the NE levels in the brain [22]. In addition, previous studies found altered DBH activity in cerebrospinal fluid (CSF) [22], also suggesting that DBH might participate in the pathological mechanism of PD.…”

“…The DBH enzyme is an important member of the DA system, and evidence has shown that under certain conditions, DBH can influence the NE levels in the brain [22]. In addition, previous studies found altered DBH activity in cerebrospinal fluid (CSF) [22], also suggesting that DBH might participate in the pathological mechanism of PD. However, little is known about how the DBH gene modulates DBH enzymatic activity as well as NE levels and further determines the retrogression of dopaminergic neurons in the development and progression of PD.…”

“…These studies were published from 1996 to 2016. Among them, 25 studies involved Caucasian populations (AD: n = 5 [20][21][22], PD: n = 3 [28][29][30], SCZ: n = 17 [34-37, 44-46, 48]), and 16 studies involved Asian populations (AD: n = 2 [23,24], PD: n = 4 [31][32][33], SCZ: n = 10 [38-43, 47, 49]). Additionally, two diagnostic criteria were used among the AD studies included (DSM-IV [56] and NINCDS-ADRDA [57]), two criteria were used for PD studies (UK PD Society Brain Bank Clinical Diagnostic Criteria (UK-PDSBB) [58] and Standard for Second National conference on Cone Diseases), and three criteria were used for SCZ studies (DSM-IV [56], DSM-III-R [56] and ICD-10 [59]).…”

“…Existing in both soluble and membrane-bound forms, DBH is the only catecholamine synthetase that is expressed in synaptic vesicles [25]. The enzymatic activity of DBH modulates NE levels and further influences executive and motor function as well as reward perception in humans [22], characterized by wide interindividual variation regulated by genetic inheritance [27]. The DBH gene, located in the chromosomal region 9q34 and also known as dopamine beta-monooxygenase (DBM), has an approximately 23 kb sequence that comprises 12 exons.…”