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  EASTBIO: Investigating the interaction between microglia, inflammation and neuronal health in iPSC-organoid models of tauopathy

   College of Medicine and Veterinary Medicine

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  Dr Kathryn Bowles, Dr B McColl  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Primary tauopathies, such as Frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) are age-related disorders characterised by both neuronal and glial accumulation of tau protein, and subsequent synaptic dysfunction and death. While neuroinflammation is a key characteristic of both disorders and correlates with neurodegeneration and cognitive decline, it is not entirely clear the extent to which tau accumulation and synaptic dysfunction induce inflammation, or whether aberrant inflammation results in neuronal damage and acceleration of pathology.

Recently, microglia have been proposed to contribute to tauopathy by promoting spread of tau seeds throughout the brain from the aberrant engulfment of live neurons or synapses containing accumulated pathogenic tau protein. However, it is unclear how an inflammatory state contributes to this process, whether neuronal or synaptic tau induces this behaviour, or whether cell-autonomous microglial properties or activation from other factors initiate synaptic pruning and neuronal ingestion.

We have recently demonstrated that astrocytes carrying a pathogenic MAPT mutation have an increased inflammatory state in the absence of any extraneous stimuli, and have an increased propensity to internalise and accumulate exogenous tau. We hypothesise this will also be the case for microglia, and predict that pathogenic mechanisms of tauopathy will be a result of the interaction between cell-autonomous microglial characteristics with non-cell autonomous responses to neurons expressing pathogenic tau.

The aim of this project is to elucidate the interaction between microglial inflammation and pathogenic tau on neuronal health and survival in iPSC-organoid models of FTD. This will be achieved using an interdisciplinary approach combining transcriptomics, iPSC modelling and microglial biology, as part of a new collaboration between Drs. Bowles and McColl. We have multiple different MAPT mutation iPSC lines with CRISPR-corrected isogenic controls for use in this study. We will first determine the cell autonomous effects of MAPT mutations on inflammation and phagocytosis in 2D iPSC-derived microglial monocultures using transcriptomic, biochemical and live-cell imaging assays. This will be followed by assessment of the interaction between iPSC-derived neuronal synaptosomes containing pathogenic tau and microglial activation. Finally, we will study the effect of MAPT mutation on microglial infiltration and neuronal dysfunction in 3D iPSC-cortical organoid models, with the goal of assessing the importance of microglial function on neuronal health, and vice versa, in FTD. This will be achieved using 3D microscopy techniques, electrophysiology and live cell imaging. Achieving these aims will result in new information regarding the contribution of microglial inflammation on the pathogenesis of frontotemporal dementia.

Biological Sciences (4)

Funding Notes

Funding information and application procedures:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP)
EASTBIO Application and Reference Forms can be downloaded via
Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]
You should also ensure that two references have been send to [Email Address Removed] by the deadline using the EASTBIO Reference Form.


1. Malpetti et al. Brain 146 (2023)
2. Wang et al. Nat Commun 13 (2022)
3. Bowles, et al. bioRxiv 2023.06.02.543224 (2023)
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