"My group aim to understand how, when, and where endothelial cells and pericytes lining the blood-brain barrier become dysfunctional in the early stages of age-related cognitive decline using cutting-edge brain imaging technology. Our ultimate goal is to develop precise treatments targeting brain vasculature to protect brain functions." Axel Montagne
UK DRI Group Leader
Dr Axel Montagne joined the UK DRI at Edinburgh in December 2020. He completed his PhD degree at the University of Caen Normandy (France) in 2012, followed by postdoctoral training at the University of Southern California (USC) in Los Angeles from 2013 to 2016. Axel rapidly became Assistant then Associate Professor at USC in 2016 and 2020, respectively. His career has focused on how cerebrovascular dysfunctions contribute to neurodegeneration and dementia in both animal models and humans. In this UK DRI programme, he combines molecular approaches with rodent non-invasive imaging, particularly MRI and PET, to study the causes and effects of blood-brain barrier (BBB) dysfunction, with a particular focus on the pericyte-endothelial crosstalk, in the context of neurodegenerative disease.
1. At a glance
Our brain is an energy-hungry organ surrounded by a rich network of blood vessels supplying the oxygen and nutrients required to function. It is essential that the microenvironment in the brain is finely controlled, and this is achieved through the specialist blood-brain-barrier (BBB) structure. However, dysfunction of the BBB is recognised as one of the earliest events in the progression of brain disorders that cause dementia, and scientists are working to understand why this occurs.
Dr Axel Montagne has previously discovered that one type of cell within the BBB, the pericyte, is particularly affected during disease and he aims to fully understand the consequences to the BBB and brain health as a whole. Using a combination of advanced molecular and imaging techniques including MRI, Dr Montagne seeks to uncover the disease mechanisms at play and identify therapeutic targets for intervention.
2. Scientific goals
A growing body of literature supports the involvement of blood-brain barrier (BBB) dysfunctions in the early stages of brain disorders such as small vessel disease (SVD) and Alzheimer’s disease (AD). In particular, researchers are interested in the role played by pericytes, cells that wrap around endothelial cells and are important for blood vessel formation, BBB maintenance, regulation of immune cell entry into the central nervous system (CNS) and control of brain blood flow.
Dr Axel Montagne has published numerous human studies providing evidence of a critical role for pericytes in the progression of diseases that cause dementia. He has previously shown that there is an age-dependent BBB breakdown in the human hippocampus, which worsens with mild dementia and correlates with injury to BBB-associated cell pericytes, pericyte dysfunction and BBB breakdown are early biomarkers of human cognitive decline, and BBB breakdown in individuals carrying the ε4 allele of the apolipoprotein E (APOE) gene, a major genetic risk factor for AD, increases with and predicts cognitive impairment.
Dr Montagne’s work in animal models has taken these investigations further, demonstrating that pericyte deficiency leads to capillary breakdown initiating early white matter damage, in part due to blood-derived neurotoxic fibrinogen extravascular deposits, and that acute ablation of brain pericytes leads to capillary disruption which triggers a rapid brain circulatory failure and neuronal loss in part due to loss of a pericyte-derived growth factor called pleiotrophin.
With the role of pericytes in brain disorders established, fundamental mechanistic insights must now be uncovered. Questions still remain as to what can cause pericytes to become dysfunctional and ultimately die, and how pericyte loss in turn destabilises the endothelial cells lining the BBB. Greater knowledge in these areas may lead to novel therapeutic targets for cerebrovascular stabilisation in chronic neurodegenerative disease.
Main objectives and research goals:
In this UK DRI research programme, Dr Montagne aims to address these questions by combining advanced molecular approaches with rodent non-invasive imaging, e.g., MRI and PET. He hypothesises that endothelial activation at the BBB is an early trigger for pericyte dysfunction and intends to better understand the consequences of this to the BBB as a whole. Specifically, he will:
1. Assess the impact of modulating both pericyte and endothelial cell functions to define the downstream consequences for the other cell type, and for BBB functions
2. Determine the role of resident microglia and systemic immune cells in responding to a compromised endothelium-pericyte interplay, and their contribution to BBB integrity
3. Test BBB preserving interventions in an in vitro platform
4. Define the impact of vascular-targeted therapeutic interventions for ameliorating vascular, neuronal, and cognitive functions in the context of SVD & AD
3. Team members
Dr Audrey Chagnot (Postdoctoral Researcher)
Dr Conor McQuaid (Postdoctoral Researcher)
Daniela Jaime Garcia (Wellcome Trust Translational Neuroscience PhD Student)
Within UK DRI:
- Prof Joanna Wardlaw (UK DRI at Edinburgh)
- Prof Anna Williams (Co-investigator, UK DRI at Edinburgh)
- Dr Barry McColl (UK DRI at Edinburgh)
- Dr Blanca Díaz-Castro (UK DRI at Edinburgh)
- Dr Jian Gan (UK DRI at Edinburgh)
- Dr Gabriel Balmus (UK DRI at Cambridge)
Beyond UK DRI:
- Prof Berislav Zlokovic (University of Southern California)
- Dr Zhen Zhao (University of Southern California)
- Prof Viviana Gradinaru (California Institute of Technology)
- Dr Alexandre Bonnin (University of Southern California)
- Prof Karen Horsburgh (University of Edinburgh)
- Prof Roxana Carare (University of Southampton)
- Dr Adriana Tavares (University of Edinburgh)
Blood-brain barrier (BBB), endothelial cells, pericytes, vascular biology, neuroinflammation, neurodegeneration, cognition, dementia
In vivo models, magnetic resonance imaging (MRI), positron emission tomography (PET), in vivo multiphoton imaging, transcriptomics, behavioural assessment, blood-brain barrier in vitro models
7. Key publications
Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D'Orazio LM, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Reiman EM, Caselli RJ, Chui HC, Tcw J, Chen Y, Pa J, Conti PS, Law M, Toga AW, Zlokovic BV. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020 May;581(7806):71-76. doi: 10.1038/s41586-020-2247-3. Epub 2020 Apr 29. PubMed PMID: 32376954; PubMed Central PMCID: PMC7250000.
Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazic D, Sweeney MD, Kong P, Wang M, Owens NC, Lawson EJ, Xie X, Zhao Z, Zlokovic BV. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nat Neurosci. 2019 Jul;22(7):1089-1098. doi: 10.1038/s41593-019-0434-z. Epub 2019 Jun 24. PubMed PMID: 31235908; PubMed Central PMCID: PMC6668719.
Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019 Feb;25(2):270-276. doi: 10.1038/s41591-018-0297-y. Epub 2019 Jan 14. PubMed PMID: 30643288; PubMed Central PMCID: PMC6367058.
Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, Barnes SR, Daianu M, Ramanathan A, Go A, Lawson EJ, Wang Y, Mack WJ, Thompson PM, Schneider JA, Varkey J, Langen R, Mullins E, Jacobs RE, Zlokovic BV. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med. 2018 Mar;24(3):326-337. doi: 10.1038/nm.4482. Epub 2018 Feb 5. PubMed PMID: 29400711; PubMed Central PMCID: PMC5840035.
Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med. 2017 Nov 6;214(11):3151-3169. doi: 10.1084/jem.20171406. Epub 2017 Oct 23. Review. PubMed PMID: 29061693; PubMed Central PMCID: PMC5679168.
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015 Jan 21;85(2):296-302. doi: 10.1016/j.neuron.2014.12.032. PubMed PMID: 25611508; PubMed Central PMCID: PMC4350773.