Meet the team

Barry McColl

"I am very grateful and inspired to be a part of the UK DRI. With the backing of the institute, my team and I look forward to making important advances in knowledge that can help us tackle the huge challenge of treating and preventing diseases causing dementia." Barry McColl
UK DRI Group Leader

With expertise in neuroimmune biology and inflammation, Dr Barry McColl’s work aims to identify new treatment targets in this exciting field. Obtaining his PhD in Neuroscience from the University of Glasgow in 2004, he went on to complete postdoctoral training at the University of Manchester, joining The Roslin Institute at the University of Edinburgh in 2010 as a Tenure-track Fellow. He joins the UK DRI at Edinburgh to lead a novel programme of research investigating how microglia influence resilience and susceptibility to neurodegenerative and vascular diseases that are causes of dementia.

1. At a glance

Investigating the role of microglia in dementia-causing diseases

Dr Barry McColl is studying the role of specialised immune cells within the brain, called microglia, in neurodegenerative and cerebrovascular disease. His goal is to gather new knowledge about which of their activities are harmful or helpful, and how this is controlled, paving the way to potential new treatments for dementia.

Microglia act as the brain’s sentry guards, seeking out potential threats. Once activated, they remove waste materials, dead cells or foreign invaders by engulfing them – and also enlist the help of other immune cells, leading to inflammation of the surrounding brain tissue. They also perform important “housekeeping” functions to maintain a healthy brain environment.

Overactive microglia and inflammation, that may arise from certain states of activated microglia, are a feature of many neurodegenerative diseases, including common forms of dementia such as Alzheimer’s disease (AD). But it remains unclear if the microglia’s disrupted function and inflammation is a root cause of disease or is a response to other triggers, such as the accumulation of abnormal proteins or death of neurons – other hallmarks of many neurodegenerative diseases.  Equally, it is emerging that insufficient or failed protective functions of microglia may also be involved in diseases leading to dementia. Understanding how the balance in microglial activity is controlled and how to optimise this therapeutically is an important target for therapy.

Barry and his team are investigating how tiny waste-recycling structures inside microglia, called lysosomes, may be involved in neurodegenerative diseases. They are also studying how microglia contribute to rare conditions known as ‘microgliopathies’, which are the most direct current evidence for failed microglia as causes of neurological disease – this will shed new insight into their biological functions and be instructive for how they may be involved in more common dementias. Finally, the group are also developing innovative new tools and techniques that will help advance the study of microglia and inflammation in neurodegenerative diseases.

2. Scientific goals

This UK DRI programme, led by Dr Barry McColl, will contribute answers to some of the most pressing questions regarding the involvement of microglia and neuroinflammatory processes in neurodegenerative disease. The overall scientific goal is to identify key microglial mechanisms influencing resilience and susceptibility to dementia-causing disease that could be manipulated for therapeutic intervention.

Microglia perform important developmental, homeostatic and neuroimmune functions and growing evidence supports that aberrations in each of these broad functional domains can contribute to neurological dysfunction across the lifespan, including dementia-causing neurodegenerative disease. The discovery of a set of neurodegenerative diseases where the primary disease-causing mechanism appears to be a fault in microglial function (“microgliopathies” e.g. Nasu-Hakola disease (NHD) caused by TREM2/TYROBP mutations and ALSPs caused by CSF1R mutations) supports causative roles. Mutations in TREM2 and other microglial-enriched genes also increase the risk of Alzheimer’s disease (AD) and other neurodegenerative conditions.

The discovery of a subtype/sub-state of microglial cells emerging during the progression of different neurodegenerative disease models has brought new insight to the phenotypic alterations that occur in microglia in disease, importantly showing these are not conventional inflammatory changes. A striking observation in the disease–associated microglial (“DAM”) gene cluster is its enrichment for lysosomal genes. The team are conducting functional studies to determine roles of candidate microglial lysosomal pathways, and more broadly, are seeking to track microglial lysosomal changes during the course of neurodegenerative disease.

In most paradigms of neurodegenerative disease, microglial involvement may be elicited by other triggers. Microgliopathies, in contrast, appear to result from primary microglial dysfunction in the absence of other overt triggers. In addition to being critical disorders to understand themselves, mechanistic insight will shed light on how dysregulated microglia can contribute to sporadic disorders more broadly. A notable common feature of several these conditions is the predominant white matter pathology. The work in this programme will bring insight to white matter microglial phenotypes and dementia-relevant microglial-white matter component interactions. It will also enable comparisons across different paradigms of neurodegenerative disease in which microglial dysfunction may be disease-influencing as a primary trigger vs secondary modifier.

Main objectives and research goals:

1. To determine how neurodegenerative disease affects microglial lysosomal properties and the impact of altered microglial lysosomal function.

2. To determine how microglial phenotype and diversity are affected during the trajectory of dementia-causing white matter disease and the impact of microglial dysregulation.

3. To develop methods and resources to enhance basic and translational study of microglial and neuroinflammatory mechanisms in neurodegenerative disease.

3. Team members

Centre staff
Ms Alexa Jury (UK DRI Centre Lab Manager)
Karen Biggar (Personal Assistant)
Ms Lynsey Dunsmore (UK DRI Centre Research Technician)
Dr Owen Dando (UK DRI Centre Senior Bioinformatician)
Dr Xin He (UK DRI Centre Bioinformatician)
Dr Katie Emilianova (UK DRI Centre Bioinformatician)
Dr Juraj Koudelka (UK DRI Centre Microscopy Facility Manager)

Lab Members
Dr Mike Daniels (Postdoctoral Researcher)
Dr Laura McCulloch (Postdoctoral Researcher)
Dr Alison Harris (Research Technician)
Adrian Olmos Alonso (Research Associate)
Lucas Lefvre (Research Assistant)
Caoimhe Kirby (PhD Student)
Clare Latta (PhD Student)
Stefan Szymkowiak (PhD Student)
Makis Tzioras (PhD Student)
James Loan (PhD Student)
Anirudh Patir (PhD student)

4. Collaborations

Within UK DRI:

  • Prof Josef Priller, UK DRI at Edinburgh
  • Prof Giles Hardinghamm UK DRI at Edinburgh
  • Prof John Hardy, UK DRI at UCL
  • Prof Siddarthan Chandran, UK DRI at Edinburgh

Beyond UK DRI:

  • Prof Karen Horsburgh, University of Edinburgh
  • Dr Martijn Verdoes, University Medical Centre Radbout, Nijmegen
  • Dr Clare Pridans, University of Edinburgh
  • Prof Colin Smith, University of Edinburgh
  • Prof Alistair Lawrence, The Roslin Institute/Scottish Rural College
  • Dr Andrea Caporali, University of Edinburgh
  • Prof Stuart Allan, University of Manchester
  • Prof Rustam Al-Shahi Salman, University of Edinburgh
  • Dr Paul Brennan, University of Edinburgh
  • Prof Sam David, McGill University, Montreal
  • Dr Andrew Greenhalgh, University of Bordeaux
  • Prof David Hume, University of Queensland
  • Prof Maria Moro, Complutense University of Madrid
  • Prof Craig Smith, University of Manchester
  • Dr Gerry Thompson, University of Edinburgh
  • Dr Lawrence Moon, King’s College London

5. Topics

Cerebrovascular disease, stroke, microglia, myeloid cells, inflammation, lysosome, white matter

6. Techniques

In vivo models, transcriptomics (including single cell RNAseq), microglia cell culture, magnetic resonance imaging (MRI), flow cytometry

7. Key publications

Patir A, Shih B, McColl BW, Freeman TC (2019). A core transcriptional signature of human microglia: Derivation and utility in describing region-dependent alterations associated with Alzheimer's disease. Glia  https://doi.org/10.1002/glia.23572 PMID 30758077

Greenhalgh AD, Zarruk JG, Healy LM, Baskar Jesudasan SJ, Jhelum P, Salmon CK, Formanek A, Russo MV, Antel JP, McGavern DB, McColl BW, David S (2018). Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLoS Biol 16:e2005264 https://doi.org/10.1371/journal.pbio.2005264 PMID: 30332405.

McCulloch L, Smith CJ, McColl BW (2017). Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke. Nat Commun 8:15051 https://doi.org/10.1038/ncomms15051 PMID: 28422126

Manso Y, Holland PR, Kitamura A, Szymkowiak S, Duncombe J, Hennessy E, Searcy JL, Marangoni M, Randall AD, Brown JT, McColl BW, Horsburgh K (2017). Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease. Glia 66:34-46 https://doi.org/10.1002/glia.23190 PMID: 28722234

Owens R*, Grabert K*, Davies CL, Alfieri A, Antel JP, Healy LM, McColl BW (2017). Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-kappaB. Front Cell Neurosci 11:56 https://doi.org/10.3389/fncel.2017.00056 PMID: 28303091

Grabert K, Michoel T, Karavalos M, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW (2016). Microglial brain region−dependent diversity and selective regional sensitivities to aging. Nat Neurosci 19:504-516 https://doi.org/10.1038/nn.4222 PMID: 26780511

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New Research Associate role with Dr Marco Brancaccio, UK DRI at Imperial - recruitment of circadian clocks in brain… https://t.co/OAhT2Vi4UA
09 Dec 2019 16:50