Mallach, Anna Katherina;
(2021)
Microglial exosome secretion coupled to TREM2: implications on neuron-like cells.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Gene-wide association studies have implicated microglia, the immune cells of the brain, in the development and progression of Alzheimer’s disease (AD), the most common form of dementia. Genetic variants on the triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing AD. TREM2 fulfils a range of different functions in microglia and this thesis investigated the contribution of TREM2 variants on the secretion, content and effect of small extracellular vesicles, exosomes, from microglia. To study this, patient-derived induced pluripotent stem cells (iPSC) carrying TREM2 variants were differentiated into microglia-like cells (iPS-Mg), using a newly developed protocol. These cells displayed microglia like functions and were shown to secrete exosomes. Exosome secretion was decreased from iPS-Mg carrying TREM2 variants, a deficit that could be rescued with increasing the energy availability in the iPS-Mg. Independent of the secretion rate, exosomal protein content was also influenced by the disease-relevant R47Hhet TREM2 variant. Proteomic analysis of exosomes, through mass spectrometry, revealed differences between exosomes from common variant (Cv) and R47Hhet iPS-Mg. Changes in the exosomal proteome were studied after iPS-Mg were exposed to either lipopolysaccharide (LPS), a classical treatment to activate microglia, or apoptotic neurons, a more physiological stimulus. Exosomes from Cv iPS-Mg showed a stimulus-specific shift in protein content, a response that was reduced in exosomes from R47Hhet iPS-Mg. The differences in exosomal protein translated to differential responses in neuron-like cells to these exosomes. As neuronal models SH-SY5Y and iPS-neurons were used and the effect of exosomes was analysed. The effect of exosomes on cell death and cell stress pathways appeared to be dependent on the treatment of iPS-Mg, whilst the TREM2 status of exosome-secreting iPS-Mg also played a role in inducing effects in metabolism and synaptic functioning in neuron-like cells.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Microglial exosome secretion coupled to TREM2: implications on neuron-like cells |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10124579 |
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