The role of myeloid cells in neurodegenerative diseases. Studies on cellular phenotype and communication.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Sammanfattning

Neurological disorders are listed as the second leading cause of death worldwide. Stroke and Alzheimer’s disease (AD) are the major contributors to neurological disorders of deaths. Every year, around 14 million new people are affected by stoke and nearly 10 million new cases of AD are diagonosed worldwide. The number of deaths and disabilities due to these disorders have increased considerably. Neuroinflammation is a major pathological feature appearing in the central nervous system (CNS) in these disorders. The central cellular components for neuroinflammation in CNS is microglia. The multifaceted roles of microglia under pathological conditions have been investigated by several research groups. Even if the knowledge about these cells is extensive, many aspects of their role in diseases have not been well elucidated. One of them is how microglia contribute to the pathology. Thus, I investigated how microglia communicate with other cells through extracellular vesicles (EVs) and how microglia cross-talk with the periphery under AD pathology.

Firstly, upon LPS activation of microglia, we found that larger sizes of EVs were released and the levels of proinflammatory cytokines, TNF and IL-6, were increased in EVs. The proteomic profile was shifted to ribosomal assembly and translation. Complete ablation of TNF expression alleviated the inflammation and lead to reduced EVs secretion in a mouse model of stroke, as well as in vitro with LPS stimulation.

Microglia are highly dynamic cells and can alter their phenotypes in response to diverse conditions. Therefore, we wanted to elucidate the activation profile of microglia under pathogenic conditions. In the early phase of AD pathogenesis, there is little known about how microglia contribute to the pathology. Thus, the 5xFAD mouse model of AD was used to investigate the effects before the formation of amyloid-β (Aβ) plaques in the CNS. Using a proteomic approach, early inflammatory activation of microglia was found before the formation of plaques.

Last but not least, we studied the cross-talk between CNS and periphery under Aβ pathology. There are conflicting findings from animal studies on the contribution of peripheral inflammation on AD due to the variations in the degree of inflammation, timepoint of the stimulation, and the duration. Therefore, we designed our study to have two timepoints wherein we modulate the innate immunity, one was at the pre-plaque stage and the other was at the postnatal stage. Strikingly, a reduced number of plaques was found in hippocampus accompanied by less microglial activation in 5xFAD mice 4.5 months after the peripheral LPS challenge during the pre-plaque state. Subsequently, single-cell sequencing demonstrated that the early inflammation at the postnatal phase affected microglia and bone marrow resident monocytes (BM-Mo) similar to how AD affects these cell types. Interestingly, unique subpopulations of microglia were identified that were enriched in genes associated with lysosomal function (Lyz2) and a detrimental inflammatory marker (Galectin-3). These particular subsets carried a BM-Mo-like phenotype and appeared in response to acute peripheral inflammation and chronic inflammation caused by AD. We also observed that some subsets of myeloid cells were provoked by Aβ pathology but not systemic inflammation and vice versa.

To summarize, microglia have multiple ways of contributing to the pathology of AD. Systemic inflammatory challenge can have pronounced effects on innate immunity in the CNS and the underlying mechanism remains to be elucidated. The findings of this thesis also provide potential candidates for use in early diagnostics and pharmacological targets to prevent the progression of AD.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för experimentell medicinsk vetenskap
Handledare
  • Deierborg, Tomas, handledare
  • Li, Jia-Yi, Biträdande handledare
  • Dunning, Christopher, Biträdande handledare
Tilldelningsdatum2021 juni 3
UtgivningsortLund
Förlag
ISBN (tryckt)978-91-8021-077-5
StatusPublished - 2021

Bibliografisk information

Defence details
Date: 2021-06-03
Time: 9:00
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/65156210635
External reviewer(s)
Name: Harris, Robert
Title: Professor
Affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Ämnesklassifikation (UKÄ)

  • Neurovetenskaper

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