Serotonin system in Alzheimer's disease : from a molecular and biomarkers perspective

Serotonin, 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter with a wide range of biological functions. It contributes to the integrity, connectivity and function of the central nervous system (CNS). Here in this thesis, we aim to understand molecular and clinical changes of the serotonergic systems in Alzheimer’s disease (AD) and related neurodegenerative diseases. We studied several aspects of the serotonin system, focusing on the 5-HT1B receptor and related molecules. Different models and samples were used to explore this, such as cell lines, transgenic animals, human platelets and brain tissues. In paper I, we showed that the 5-HT1B receptor, s100A10 (p11), 5-HT, 5-HIAA and MAO-A enzyme activity were altered in the neuroblastoma cell line, SH-SY5Y stably transfected with the human APP (amyloid precursor protein) gene with the double APP Swedish mutation (APPswe). There was a reduction of extracellular 5-HT levels measured in cell medium. Moreover, higher 5-HT degradation indices were observed in APPswe cells. A similar pattern of proteomic changes was observed in the mice model of AD (Tg2576). Expression of 5-HT1B and the serotonin transporter (SERT) are reduced in 2-year-old female mice. These findings suggest that the decrease in 5-HT1B in these models might be a compensatory biological mechanism to the decreased extracellular 5-HT levels. Together these findings indicate an effect of APPswe mutation on the serotonergic system, modulating 5-HT1B and 5-HT metabolites. In paper II, we showed that the normal compensatory upregulation of SERT gene expression, after the pharmacological blockade of 5-HT1B receptor, is lost in APPswe cells. The effect of 5-HT1B modulations on p11 gene expression is complex. Treatment with 5-HT and 5- HT1B antagonist decreases p11 gene expression in both APPswe cells and control cells. 5-HT also increases MAO-A gene expression and the production of 5-HIAA in APPswe cells. In addition, our results suggest that the MAPK signaling pathways is affected differently in APPswe by 5-HT and 5-HT1B. In contrast to control cells, sertraline, a selective serotonin reuptake Inhibitor (SSRI), reduces intracellular 5-HT levels and increases indices of 5-HT breakdown (5-HIAA/5-HT ratio) in APPswe cells. However, an inhibitory effect of sertraline on MAOA-A activity was also observed in APPswe cells. Importantly, no change on extracellular 5-HT or 5-HIAA was seen. We suggest that these changes are SERT and MAO-A-independent and could be attributed to biochemical interactions between Aβ peptides and 5-HT pathway molecules. The results, in this study, illustrate the differences in 5-HT1B-related molecules in AD and physiological models when extracellular 5-HT levels and 5-HT1B receptor are modulated. viii In papers III and IV we explored the association of the serotonergic markers to cognitive decline, synaptic biomarkers and pathological changes in people with dementia. In paper III, we demonstrated that AD patients have lower 5-HT levels in their medium-density platelet fractions compared to the group with subjective cognitive impairment (SCI). In the SCI group, those with low platelets 5-HT have higher cerebrospinal fluid (CSF) total tau and tau/Aβ42 ratio than those with high 5-HT. These findings suggest that platelet 5-HT has a potential for being an early proxy for CSF biomarkers in AD. In paper IV, our results showed alteration in 5-HT1B levels in the postmortem prefrontal cortex (PFC) of people with AD and other dementias, including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Higher levels of 5-HT1B were observed in AD and DLB groups. Furthermore, 5-HT was reduced in DLB, and 5-HIAA was low in all dementia groups. There were significant associations between 5-HT and pathological markers and synaptic proteins in DLB. Higher 5-HT1B levels were associated with more rapid cognitive decline in AD, PDD and combined dementia group. The study indicates an association between prefrontal 5-HT1B levels and cognitive decline in dementia. Furthermore, it suggets a potential benefit of 5-HT1B antagonists in enhancing memory function in dementia