Defining vascular-immune cell heterogeneity and and intercellular communication in human vascular disease and dementia

Precision Medicine Project - Defining vascular-immune cell heterogeneity and and intercellular communication in human vascular disease and dementia

Supervisor(s): Prof Karen Horsburgh, Dr Jill Fowler Dr Owen Dando, Prof. Raj Kalaria (Newcastle University)
Centre/Institute: Centre for Discovery Brain Science

Abstract:

Cerebral white matter abnormalities are key predictors of Vascular Dementia and Alzheimer’s Disease, driven by vascular dysfunction including cerebral hypoperfusion. However, the pathways linking white matter dysfunction to cognitive decline remain unclear, hindering effective treatments. Our research using human post-mortem tissues and animal models has identified mechanisms such as microglial disruption, endothelial dysfunction, blood-brain barrier breakdown, and microvascular inflammation as contributors to white matter damage. Our studies suggest that microglial states (abundance/function) influence white matter abnormalities through interactions with endothelial cells, necessitating deeper investigation into microglial diversity.

This PhD project aims to further explore vascular-immune cell heterogeneity and their interactions in human Vascular Dementia, using a unique cohort of well-characterized post-mortem brain tissues. The cohort, assessed with neuropsychometric tests and neuroimaging, includes data on white matter abnormalities linked to cognitive status. Age-matched controls will serve as a comparison group. The project will focus on single-cell approaches (e.g., snRNA sequencing, spatial transcriptomics) and pathology to examine microglia-endothelial cell diversity and communication, and their association with white matter changes and cognition. These studies aim to identify novel immunomodulatory targets for early intervention to slow cognitive decline in Vascular Dementia.

References:

  1. Patir A, Barrington J, Szymkowiak S, Brezzo G, Straus D, Alfieri A, Lefevre L, Liu Z, Ginhoux F, Henderson NC, Horsburgh K, Ramachandran P, McColl BW. Phenotypic and spatial heterogeneity of brain myeloid cells after stroke is associated with cell ontogeny, tissue damage, and brain connectivity. Cell Rep. 2024 May 17;43(5):114250. doi: 10.1016/j.celrep.2024.114250. 
  2. Askew KE, Beverley J, Sigfridsson E, Szymkowiak S, Emelianova K, Dando O, Hardingham GE, Duncombe J, Hennessy E, Koudelka J, Samarasekera N, Salman RA, Smith C, Tavares AAS, Gomez-Nicola D, Kalaria RN, McColl BW, Horsburgh K.  Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment. Glia. 2024 72(2):375-395. doi: 10.1002/glia.24481.  
  3. McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J, Miron VE. Microglia regulate central nervous system myelin growth and integrity. Nature. 2023 613(7942):120-129. doi: 10.1038/s41586-022-05534-y. 
  4. Hase Y, Horsburgh K, Ihara M, Kalaria RN. White matter degeneration in vascular and other ageing-related dementias. J Neurochem. 2018 144(5):617-633. doi: 10.1111/jnc.14271. 

Background

Dementia, affecting nearly 1 million people in the UK, leads to progressive cognitive decline and impairment in daily activites. With rising cases and no effective treatments, understanding early disease mechanisms is urgently needed for better therapies. Damage to brain vasculature and reduced blood flow are early drivers of Alzheimer’s Disease and Vascular Dementia (VaD), leading to white matter damage (bundles of myelinated nerve fibres that connect different brain regions, vital for cognition). White matter abnormalities, detectable by neuroimaging, are common with aging, predict vascular cognitive impairment, and increase Alzheimer's risk three-fold.

Our previous work, using both human VaD tissue and a clinically relevant tractable mouse model, suggests that disruption to microglia, the brain’s immune cell, and brain endothelial cells and their intercellular communication plays a key role in promoting white matter changes [1-4]. The PhD proposal will develop this research to test the hypothesis ‘altered microglia-endothelial cell state and intercellular communication drives white matter pathology and cognitive decline in dementia’.

Aims and methods

  1. Determine alterations to microglia and endothelial state and intercellular signalling using snRNA seq of human vascular dementia 

    A unique prospectively clinically characterised human post-mortem cohort (Cognitive Function After STroke, CogFAST) will be studied. The cohort is well phenotyped using neuropsychometric batteries to diagnose VaD and neuroimaging to define white matter abnormalities. The latest advances in single nuclear approaches (snRNA sequencing) will be undertaken and data provided for analysis by the student.  The project  will focus on endothelial cells, microglia and other brain myeloid cells from frontal white matter and use established computational methods to compare the extent of cellular heterogeneity in samples from those individuals with and without VaD post-stroke compared to age-matched controls; the molecular pathways underpinning this heterogeneity will be examined in an unbiased way. Furthermore, bioinformatic tools will be used (CellChat) to quantitatively examine intercellular communication  to provide novel  insight to microglia-endothelial cell  communication and disruption in VaD including stratifying individuals based on imaging or cognitive status comparing those measures to transcriptomic differences in endothelial cells/microglia and alongside white matter differences. 

  2. Determine spatial alterations to microglial and endothelial state and intercellular signalling in human vascular dementia 

    Following on from snRNAseq. of cell subtypes the next aim will be to  provide spatial information on the endotheial cell-microglia axis using paraffin sections obtained from the CogFAST cohort.  It is envisaged a  custom Xenium prime 5k human pathways panel will be used, which includes a battery of genes relevant to microglia and endothelia alterations in disease. Single cell-imaging will be carried out at UofE Single-cell multi-omics facility (CRM). Spatiotemporal alterations in white matter  abnormalities will be analysed in relation to microglia-endothelial cell subtypes/state using approaches similar to Aim 1 above including investigating ligand-receptor interactions.  Alterations to proteins of interest based on the results will be validated in paraffin embedded adjacent to the tissue sections used for spatial transcriptomics.

    As a complementary approach the student could determine how the expression of the gene sets compare to those reported in databases for endothelial cells and myeloid cells in brain and in dementia such as Alzheimer’s disease. 

Training outcomes

We aim to equip the student with specialized skills in dementia-related neuroscience, including snRNAseq analysis, molecular and cellular imaging, and computational analysis, supported by neuroinformatics experts supervisor Dr. Owen Dando and Dr. Eleni Papachristoforou. Training will also cover transferable skills like experimental design, data management, and communication. The student will engage in public outreach, such as lectures and events with dementia communities, and work within a cross-disciplinary team specialising in immune mechanisms and vascular biology. With additional support from post-doctoral researchers, the student will benefit from an NIH-funded program (2023-2028) led by Fowler and Horsburgh, in collaboration with the University of Newcastle, offering a rich environment for advancing dementia research and training.

Apply Now

Click here to Apply Now

  • The deadline for 25/26 applications is Monday 13th January 2025
  • Applicants must apply to a specific project. Please ensure you include details of the project on the Recruitment Form below, which you must submit to the research proposal section of your EUCLID application. 
  • Please ensure you upload as many of the requested documents as possible, including a CV, at the time of submitting your EUCLID application.  

 

Q&A Sessions

Supervisor(s) of each project will be holding a 30 minute Q&A session in the first two weeks of December. 

If you have any questions regarding this project, you are invited to attend the session on TBC via Microsoft Teams. Click here to join the session.

This article was published on