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Neuroinflammation and its resolution in Alzheimer's disease

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posted on 2024-09-02, 17:35 authored by Ying Wang

Alzheimer's disease (AD) is the most common dementia with high prevalence among an increasing aged population. Despite the existence of symptom-reliving drugs for AD, the clinical trials performed until now have failed to find drugs that cure or stop the progression of AD. New perspectives and strategies for treatments are therefore direly needed. Chronic inflammation as indicated by persistent activation of microglia and increased proinflammatory mediators is one of the major characteristics for AD, together with pathological accumulation of β-amyloid (Aβ), hyperphosphorylated tau proteins and neuronal loss. In normal physiological conditions, inflammation is ended by resolution, an active process associated with restoration and regeneration mediated by specialised pro-resolving lipid mediators (SPMs). Previous studies have shown that there are alterations in the resolution of inflammation in AD that can cause neurodegeneration by impairment in neuroprotective signalling, control of inflammation, and in the removal of the pathogenic Aβ peptide. The current studies focus on the impairment of pro-resolving mechanisms in the context of AD. The prospect of reducing harmful inflammation while at the same time increasing protective and pro-homeostatic activities present a promising strategy for treating AD.

In Paper I and II, we focused on answering the fundamental question, whether and how the neuroinflammation (Paper I) and its resolution (Paper II) are altered in AD patients. We aimed to identify dissimilar inflammation-related protein mediators (Paper I) and SPMs (Paper II) profiles in the cerebrospinal fluid (CSF) of patients diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) or AD. We found an inflammatory pattern in the CSF that could differentiate SCI and AD. Comorbidities have an influence on the inflammatory pattern. SPMs were decreased in the CSF of AD patients and were associated with AD pathologies and cognition, suggesting that SPMs have potential to be novel biomarkers for AD. In Paper III and IV, the aim of the studies was to explore the pro-resolving role of maresin 1 (MaR1) in the context of Aβ42-induced inflammation in human microglial cell models. In Paper III, AD-like neuroinflammation was induced exposure to Ab42 monomers in both human monocyte-derived microglia (MdM) and a differentiated human monocyte cell line (THP-1 cells). We showed that one of the SPMs MaR1 reduced Aβ42-induced elevation in pro-inflammatory activation and stimulated the Aβ42 uptake. In Paper IV, RNA-Sequencing (RNA-Seq) was used to study the effects of MaR1 on the transcriptome of Aβ42-treated MdM to obtain a broader view regarding the pro-resolving roles of MaR1. We found that Aβ42 up-regulated inflammatory pathways and that co-incubation with MaR1 down-regulated some of these pathways. Proteomics confirmed the finding.

In conclusion, the inflammation-related protein mediator profile and SPMs in CSF have a potential to contribute to the diagnosis of AD and are correlated to AD pathologies and cognition. SPM MaR1 attenuates AD-like neuroinflammation and supports the hypothesis that stimulating the resolution of inflammation could be a new therapeutic strategy in AD.

List of scientific papers

I. Ying Wang, Ceren Emre, Helena Gyllenhammar-Schill, Karin Fjellman, Helga Eyjolfsdottir, Maria Eriksdotter, Marianne Schultzberg, Erik Hjorth. Cerebrospinal fluid inflammatory markers in Alzheimer’s disease: influence of comorbidities. Curr Alzheimer Res. 2021.
https://doi.org/10.2174/1567205018666210330162207

II. Khanh V. Do, Erik Hjorth, Ying Wang, Bokkyoo Jun, Marie-Audrey I. Kautzmann, Maria Eriksdotter, Marianne Schultzberg, Nicolas G. Bazan CSF profile of lipid mediators in Alzheimer’s disease. [Manuscript]

III. Ying Wang, Axel Leppert, Shuai Tan, Bram van der Gaag, Nailin Li, Marianne Schultzberg, Erik Hjorth. Maresin 1 attenuates pro-inflammatory activation induced by b-amyloid and stimulates its uptake. J Cell Mol Med. 2021;25(1):434-447.
https://doi.org/10.1111/jcmm.16098

IV. Ying Wang, Xiang Zhang, Henrik Biverstål, Nicolas G. Bazan, Shuai Tan, Xiaofei Li, Nailin Li, Marianne Schultzberg, Erik Hjorth. Pro-resolving lipid mediator reduces Ab42-induced gene expression in monocyte-derived microglia. [Manuscript]

History

Defence date

2021-06-23

Department

  • Department of Neurobiology, Care Sciences and Society

Publisher/Institution

Karolinska Institutet

Main supervisor

Hjorth, Erik

Co-supervisors

Schultzberg, Marianne; Eriksdotter, Maria

Publication year

2021

Thesis type

  • Doctoral thesis

ISBN

978-91-8016-241-8

Number of supporting papers

4

Language

  • eng

Original publication date

2021-05-31

Author name in thesis

Wang, Ying

Original department name

Department of Neurobiology, Care Sciences and Society

Place of publication

Stockholm

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