UCL Birkbeck MRC DTP

Impact of novel activating antibodies targeting microglial TREM2 in a human triculture AD model

Impact of novel activating antibodies targeting microglial TREM2 in a human triculture AD model
Professor Jennifer Pocock (UCL Queen Square Institute of Neurology) and Dr Michael Perkinton (AstraZeneca, Cambridge, UK)

The Project

Microglia, the immune cell of the brain, express the protein triggering receptor expressed on myeloid cells-2 (TREM2). Immune dysfunction linked to the microglial TREM2 R47Hhet variant increases late-onset Alzheimer’s disease (LO-AD) risk, the most prevalent form of AD. TREM2 R47Hhet is a loss of function variant and TREM2 is a hub gene controlling microglial processes. Thus, understanding the ramifications of this variant to microglial function will allow progress towards therapies for LO-AD. Furthermore, enhancing TREM2 function in common variant (CV) expressing microglia may prove fruitful as a therapeutic target for other neurological diseases where microglial dysfunction is implicated. Dementia cases (with AD the most prevalent) are set to rise to 1 million in the UK by 2030, with predicted extensive societal and economic impact.  UCL (Pocock lab) has reported that patient derived R47Hhet expressing iPSC-derived microglia (iPS-Mg) display functional deficits in signalling, metabolic pathways and Aβ phagocytosis. We have interrogated these processes with novel compounds in collaboration with AstraZeneca.  We have also established cultures of iPS-neurons and iPS-astrocytes. The overarching aim of this project is to determine the outcomes of targeting microglial TREM2 with novel AstraZeneca compounds in a human AD microglial/astrocyte/neuron triculture “disease-in-a-dish” model, to further our understanding of drugs for the treatment of LO-AD. The rationale of developing microglial TREM2 as a therapeutic target is because microglia are implicated in early responses in a wide range of neurodegenerative diseases, including AD. Thus, boosting TREM2 responses (which we show is beneficial to microglial function) is likely to benefit many patients and targeting early disease stages allows more potential cognitive rescue.

During this 4 year PhD studentship, the student will establish tricultures of human iPSC derived microglia/astrocytes/neurons from cell lines expressing TREM2 variants linked to LO-AD and use cellular assays such as metabolic Seahorse assays, FACS analyses of phagocytosis, cell population and phenotypic markers by super resolution Nanoimaging microscopy, single-cell imaging, Ca2+/FLIPR platforms, transcriptomic (eg RNAseq) and proteomic assays, eg cytokine array analyses, high throughput omics platforms (including transcriptomics/RNA-seq, metabolomics and proteomic facilities including ELISA, HTRF, and MSD assay platforms for protein analysis at AstraZeneca) . The student will have the opportunity of industrial placements to undertake research in the laboratories at AstraZeneca, Cambridge, gaining insight into both academic-led research and industry-based research. During their AstraZeneca placements, the PhD student will experience excellent scientific and technical training with core bioscience skills from industrial supervisors and laboratory scientists delivered in state-of-the art research facilities. The studentship comes with a supplemented stipend (on top of the UK MRC London stipend) of £3000 per annum together with contributions towards conference attendance and project running costs, as well as all costs covered during AstraZeneca placements.

References

1. Wei, J et al., (2023) Glia 71(4): 1036

2. Popescu AS et al., (2023) Glia 71(4): 974

3. Mallach A et al., (2021) Brain Comms 3(2)2, 2021, fcab041

4. Cosker K et al., (2020)  Scientific Reports 11:12216

5. Piers TM et al., (2020) FASEB J 34(2) 2436-2450

6. Pocock JM & Piers TM (2018) Nature Rev Neurosci 19:445-452

7. Garcia Reitboeck P et al., (2018) Cell Rep 24(9):2300-2311

8. Xiang X et al., (2018) Mol Neurodegen 13:49-63

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