https://ukdri.ac.uk/team/axel-montagne
https://montagnelab.com
https://www.ed.ac.uk/clinical-brain-sciences/research/row-fogo-centre

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.

I have published numerous human studies providing evidence of a critical role for pericytes in the progression of diseases that cause dementia. I have 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.

My 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.

The overall goal of our research is to understand how cerebrovascular dysfunctions contribute to neurodegeneration and dementia in order to identify new targets for treatments.

Our work combines molecular approaches with rodent non-invasive imaging, particularly MRI & PET, to study the causes & effects of blood-brain barrier (BBB) dysfunction in the context of neurodegenerative disease. BBB dysfunction is a major cause of inflammatory & bioenergetic deregulation in the brain, but the interplay between pericytes & endothelial cells that causes this collapse is not fully delineated. We are currenlty focusing on probing BBB function & pericyte-endothelial crosstalk, especially the consequences of pericyte dysfunction on endothelial cells & the BBB, plus reciprocal signaling by activated endothelial cells.

Key research aims:

• 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

• Determine the role of resident microglia and systemic immune cells in responding to a compromised endothelium-pericyte interplay, and their contribution to BBB integrity

• Test BBB preserving interventions in an in vitro platform

• Define the impact of vascular-targeted therapeutic interventions for ameliorating vascular, neuronal, and cognitive functions in the context of SVD & AD

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.

We have previously discovered that one type of cell within the BBB, the pericyte, is particularly affected during disease and we aim 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, we seek to uncover the disease mechanisms at play and identify therapeutic targets for intervention.

1. Commentary on Saridin et al. Brain amyloid β, cerebral small vessel disease and cognition: A memory clinic study. Neurology. 2020;10.1212/WNL.0000000000011029. https://journals.lww.com/neurotodayonline/Fulltext/2020/11050/Alzheimer_s_and_Cerebral_Small_Vessel_Disease.4.aspx.
2. Dr. Axel Montagne, Associate Professor of Research Physiology & Neuroscience, weighs in on whether the dementia gene could increase risk of COVID-19: https://www.beingpatient.com/apoe4-dementia-gene-covid19-risk/?fbclid=IwAR3-G42ur1zA_s_4-LF8j74Mf4KgkLg2Y760dOADh6bjKkWXmLwZ9i_qva4.
3. Facebook Live discussing “Alzheimer's, Inflammation, and Covid-19” with Drs. Axel Montagne and Caleb Finch, organized by Leigh Hopper (Media Relations Specialist at the University of Southern California), June 24^th, 2020 (https://www.facebook.com/usc/videos/2523996221245126).
4. “ISTAART Journal Club: Meet the Author webinar”. Montagne et al., Nature 2020 “APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline” was selected by Dr. Ozama Ismail (OHSU). Q&A with Drs. Axel Montagne and Berislav Zlokovic.
5. ApoE4 damages protective barrier of the brain. https://www.beingpatient.com/apoe4-damages-protective-barrier-of-the-brain/?fbclid=IwAR1hw0cbVT74S2qxybC4l9zuwquMvpkypZayDgQ-CFYyEO1opkFPtI15S1Q.
6. Alzheimer’s gene triggers early breakdowns in blood-brain barrier, predicting cognitive decline. https://news.usc.edu/169420/alzheimers-gene-apoe4-blood-brain-barrier-cognitive-decline-usc-research. Published 04/29/2020.
7. Half of all dementias, including Alzheimer’s, start with damaged ‘gatekeeper cells’.https://news.usc.edu/135765/half-of-all-dementias-start-with-damaged-gatekeeper-cells. Published 02/05/2018.
8. Montagne A. Video abstract: Blood-Brain Barrier Breakdown and Cognitive Impairment in Humans (CellPress). From Montagne’s article, Neuron. 85:296-302, 2015. PMID: 25611508, PMCID: PMC4350773. (http://www.cell.com/cms/attachment/2041269709/2055112227/mmc3.mp4).
9. Scans detect aging brain issues linked to dementia. http://news.usc.edu/74051/usc-scientists-find-possible-prevent-of-alzheimers-and-dementia. Published 01/21/2015.