"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 joined the UK DRI at Edinburgh in 2017 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.

Excessive or misdirected microglial activity and inflammation, that may arise from certain states of reactive 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. Malfunctioning blood vessels in around the brain may also be important triggers of microglial activity and the way microglia respond may also shape how vascular disease and events such as stroke may lead to dementia. 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 microglia sense and respond to tissue damage and stress signals, including from faulty brain blood vessels and abnormal protein aggregates, and how the involvement of tiny waste-recycling structures inside microglia, called lysosomes, may be involved in diseases leading to dementia. They are also studying how microglia contribute to rare conditions known as ‘microgliopathies’, which are the most direct current evidence for malfunctioning 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, particularly arising from cerebrovascular disease, that could be manipulated for therapeutic intervention.

Microglia detect and respond to cellular and tissue distress and damage signals through an array of sensors. While considerable attention has been given to protein aggregates as triggers of microglial reactivity, a crucial knowledge gap is our poor understanding of what and how distress signals associated with cerebrovascular dysfunction and disease induce and/or propagate microglial reactive alterations. These signals may shape microglial responses early in disease course, but with potentially chronic consequences, so represent attractive targets for intervention. The lab is examining microglial sensing of stressors relevant to vascular dementia and Alzheimer’s disease, and the mechanisms regulating their responses.

Once reactivity is triggered, microglia can adopt a variety of altered molecular and functional states, some of which emerge contemporaneously and are co-located and some which are regionally variant. The combined actions of these distinct microglial subpopulations will influence their harmful and protective effects on disease and cognition. The McColl lab is investigating the ontogenetic and functional relationships among distinct reactive microglial subsets that emerge in disease states leading to dementia.

Among reactive microglial states identified recently, it is apparent that the altered gene expression patterns underpinning these states are heavily enriched for endolysosomal pathway 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. Overall, the team aim to bring insight to mechanisms by which microglia sense, respond to and influence diseases leading to dementia, revealing targets to shape microglial responses favouring neurovascular and neuroimmune resilience to cognitive impairment

Main objectives and research goals:

Determine triggers and transducing mechanisms of microglial reactivity in pathological states underlying dementia.
Identify the ontogenetic, spatiotemporal, and functional relationships among reactive microglial states emerging during cerebrovascular and neurodegenerative disease, and their regulation.
Define how cerebrovascular and neurodegenerative disease affects microglial lysosomal properties and functional consequences of perturbing microglial endolysosomal regulators.

3. Team members

Dr Jack Barrington (Postdoctoral Researcher)
Dr Gaia Brezzo (Postdoctoral Researcher)
Dr Colin Crawford (Postdoctoral Researcher)
Dr Mike Daniels (Postdoctoral Researcher)
Dr Stefan Szymkowiak (Postdoctoral Researcher)
Dana Straus (Research Assistant)
Sarah Choi (Research Assistant)
Mila Redzic (PhD Student)

4. Collaborations

Within UK DRI:

Prof Josef Priller, UK DRI at Edinburgh
Prof Giles Hardingham UK DRI at Edinburgh
Prof John Hardy, UK DRI at UCL
Prof Siddarthan Chandran, UK DRI at Edinburgh
Prof Tara Spires-Jones, UK DRI at Edinburgh
Dr Axel Montagne, UK DRI at Edinburgh
Dr Soyon Hong, UK DRI at UCL
Prof Jules Griffin, UK DRI Co-investigator at Imperial

Beyond UK DRI:

Prof Karen Horsburgh, University of Edinburgh
Dr Martijn Verdoes, University Medical Centre Radbout, Nijmegen
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 Nesh Samarasekera, University of Edinburgh
Dr Paul Brennan, University of Edinburgh
Dr Andrew Greenhalgh, University of Manchester
Prof David Hume, University of Queensland
Prof Maria Moro, CNIC, Madrid
Prof Craig Smith, University of Manchester
Dr Gerry Thompson, University of Edinburgh
Dr Lawrence Moon, King’s College London
Prof Marion Buckwalter, Stanford University
Prof Kristian Doyle, University of Arizona

5. Topics

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

6. Techniques

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

7. Key publications

McCulloch L, Harris AJ, Malbon A, Daniels MJD, Younas M, Grainger JR, Allan SM, Smith CJ, McColl BW. (2022). Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection. Immunology http://doi.org/10.1111/imm.13553

Smith C, McColl BW, Patir A, Barrington J, Armishaw J, Clarke A, Eaton J, Hobbs V, Mansour S, Nolan M, Rice GI, Rodero MP, Seabra L, Uggenti C, Livingston JH, Bridges LR, Jeffrey IJM, Crow YJ (2020). Biallelic mutations in NRROS cause an early onset lethal microgliopathy. Acta Neuropathol 139, 947–95. https://doi.org/10.1007/s00401-020-02137-7

Davies CL, Patir A, McColl BW (2019). Myeloid Cell and Transcriptome Signatures Associated With Inflammation Resolution in a Model of Self-Limiting Acute Brain Inflammation. Front Immunol 10:1048. https://doi.org/10.3389/fimmu.2019.01048

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