Identifying dysfunctional neurotransmission in neurodegenerative disorders

Ondertitel:methodological considerations and fundamental insights

Neurodegenerative disorders (NDDs) pose an ever-increasing healthcare burden on society. Studying neurochemical disturbances in these diseases could help identify novel targets of interest and pinpoint disease biomarkers. This thesis focused on the neurochemical characterization of Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies/Parkinson’s disease dementia (DLB/PDD) and amyotrophic lateral sclerosis (ALS), primarily with respect to monoaminergic neurotransmitter systems. In addition, we addressed several methodological issues, including the influence of circadian rhythm on monoamines in cerebrospinal fluid (CSF) and plasma and the rostrocaudal concentration gradient (RCG) in CSF. We also verified whether B elements, a type of short interspersed nuclear elements, could be applied as a normalization strategy in reverse transcription quantitative PCR (RT-qPCR) experiments. We found an influence of circadian rhythm on homovanillic acid (HVA), and identified the presence of a RCG for HVA and 5-hydroxyindoleacetic acid. These findings underscored the importance of standardization of pre-analytical procedures. Furthermore, we could conclude that B elements could be adopted as normalization factors in hippocampus, but less so in cortex. We further investigated monoaminergic systems in AD and behavioral variant FTLD and found that these two NDDs are characterized by distinct serotonergic and noradrenergic systems. Next, we analyzed CSF and serum samples from patients with AD, FTLD, DLB/PDD and CONTR and noted altered 3-methoxy-4-hydroxyphenylglycol levels in DLB/PDD subjects. In addition, we confirmed that CSF and serum levels of this noradrenergic metabolite improved the AD versus DLB/PDD differential diagnosis. Because of considerable clinical, genetic and neuropathological overlap between FTLD and ALS, we analyzed CSF and serum samples for monoaminergic and kynurenergic content. A general dopaminergic disturbance was observed in FTLD and ALS subjects, while the KP did not appear to be altered in the ALS-FTLD continuum. The expression of G protein-coupled receptors (GPCRs) in brain tissue of AD and CONTR subjects was assessed using RT-qPCR. Our results indicated alterations in serotonergic and noradrenergic GPCR expression levels in limbic and frontal brain areas of AD subjects. Glutamatergic and cholinergic GPCR expression levels in the hippocampus of APP23 mice were influenced by age, but not by genotype. Protein-level analyses of the 5-HT6 receptor in the APP23 model did not show any age- or genotype effects. Taken together, this dissertation offers more insight into the neurochemical imbalance in several NDDs. Our hypotheses regarding neurochemical underpinnings of NDDs remain to be strengthened, and the biomarker potential of the investigated neurochemicals should be further confirmed.

Jaar van publicatie:2020

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open