| 1. |
- Abderhim, Walid Tajeddinn
(författare)
-
Serotonin system in Alzheimer’s disease : from a molecular and biomarkers perspective
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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. 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.
|
|
| 2. |
- Tajeddinn, Walid, et al.
(författare)
-
Association of Platelet Serotonin Levels in Alzheimers Disease with Clinical and Cerebrospinal Fluid Markers
- 2016
-
Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 53:2, s. 621-630
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Serotonin (5-HT) is involved in the pathology of Alzheimers disease (AD). Objective: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid-beta 1-42 (A beta(42)), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms. Methods: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Results: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normalization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/A beta(42) ratio (p = 0.001), compared to those with high 5-HT levels. Conclusion: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.
|
|
| 3. |
- Åström, Maria, 1959-, et al.
(författare)
-
Cytokine Measurements for Diagnosing and Characterizing Leukemoid Reactions and Immunohistochemical Validation of a Granulocyte Colony-Stimulating Factor and CXCL8-Producing Renal Cell Carcinoma
- 2018
-
Ingår i: Biomarker Insights. - : Sage Publications. - 1177-2719. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Various paraneoplastic syndromes are encountered in renal cell carcinomas. This case report illustrates that a paraneoplastic leukemoid reaction may precede the diagnosis of renal cell carcinoma and be explained by cytokine production from the cancer cells.CASE PRESENTATIONS: A 64-year-old man was referred for hematology workup due to pronounced leukocytosis. While being evaluated for a possible hematologic malignancy as the cause, he was found to have a metastasized renal cell carcinoma, and hyperleukocytosis was classified as a leukemoid reaction. A multiplex panel for measurement of 25 serum cytokines/chemokines showed highly elevated levels of granulocyte colony-stimulating factor (G-CSF) and CXCL8 (C-X-C-motif chemokine ligand 8, previously known as interleukin [IL]-8). By immunohistochemistry it was shown that the renal carcinoma cells expressed both these cytokines. Two additional, consecutive patients with renal cell carcinoma with paraneoplastic leukocytosis also showed elevated serum levels of CXCL8, but not of G-CSF. Nonparametric statistical evaluation showed significantly higher serum concentrations of CXCL8, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor, but lower interferon gamma (IFN-gamma) and IL-1 alpha, for the 3 renal cell carcinoma cases compared with healthy blood donors.CONCLUSIONS: In suspected paraneoplastic leukocytosis, multiplex serum cytokine analyses may facilitate diagnosis and provide an understanding of the mechanisms for the reaction. In the index patient, combined G-CSF and CXCL8 protein expression by renal carcinoma cells was uniquely documented. A rapidly fatal course was detected in all 3 cases, congruent with the concept that autocrine/paracrine growth signaling in renal carcinoma cells may induce an aggressive tumor phenotype. Immune profiling studies could improve our understanding for possible targets when choosing therapies for patients with metastatic renal cell carcinoma.
|
|
