Prof. Karen Horsburgh

Personal Profile

Research Overview

White matter abnormalities, a core feature of cerebrovascular disease,  are predictive of vascular cognitive impairment and greatly increase risk of Alzheimer’s disease. Despite the clinical significance of white matter abnormalities there remains no disease modifying therapeutic. Thus our studies in unique cohorts of human post-mortem tissues linked to models of vascular cognitive impairment have focussed on providing mechanistic insight to the development and progression of  white matter changes in order to find new treatment targets. We highlighted the vulnerability of white matter to vascular disturbances that involves key pathomechanisms such as disruption of microglia homeostasis, endothelial cell dysfunction, blood brain barrier breakdown and microvascular inflammation. We demonstrated the beneficial effect of immunomodulatory treatment in the development of white matter damage. Emerging evidence suggests microglia state (abundance/function) via interactions with endothelial cells influence white matter abnormalities and cognitive abilities. We are currently investigating how specific regulators of microglia state influence microglia-endothelial cell interactions in the development and progression of white matter damage in human post-mortem cohorts and in models of vascular cognitive impairment. A range of approaches are underway including single cell technologies (sc/snRNAseq. spatial multiplexed RNAscope in situ hybridisation) combined with developments in in vivo imaging including  MRI/DTI/PET  and 2P imaging within white matter.

Group Members

• Juraj Koudelka, Post-doctoral Researcher Fellow & UK DRI Microscopy Manager
• Emina Hayashida, Post-doctoral Research Fellow
• Currently recruiting post-doctoral researchers (in vivo, informatics) and PhD students

Funding

• NIH/NINDS
• Alzheimer’s Research UK
• Alzheimer’s Society
• Stroke Association
• BHF

Collaborators

• Dr.Jill Fowler (University of Edinburgh)
• Dr.Barry McColl (University of Edinburgh)
• Dr. Axel Montagne (University of Edinburgh)
• Dr. Adriana Tavares  (University of Edinburgh)
• Prof. Giles Hardingham (University of Edinburgh)
• Prof. Raj Kalaria (University of Newcastle)
• Prof. Catherine Hall (University of Sussex)

Selected Recent Publications

• 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. 2023;  doi: 10.1002/glia.24481.
• 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.
•  Alfieri A, Koudelka J, Li M, Scheffer S, Duncombe J, Caporali A, Kalaria RN, Smith C, Shah AM, Horsburgh K. Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline. J Cereb Blood Flow Metab. 2022 Feb 1:271678X221077766. doi: 10.1177/0271678X221077766.  
• Li M, Kitamura A, Beverley J, Koudelka J, Duncombe J, Lennen R, Jansen MA, Marshall I, Platt B, Wiegand UK, Carare RO, Kalaria RN, Iliff JJ, Horsburgh K. Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment. Front Aging Neurosci. 2022 13:788519.
• Hase Y, Polvikoski TM, Firbank MJ, Craggs LJL, Hawthorne E, Platten C, Stevenson W, Deramecourt V, Ballard C, Kenny RA, Perry RH, Ince P, Carare RO, Allan LM, Horsburgh K, Kalaria RN. Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction. Brain Pathol. 2020 30(1):191-202. doi: 10.1111/bpa.12769.
• Hase Y, Polvikoski TM, Ihara M, Hase M, Zafar R, Stevenson W, Allan LM, Ennaceur A, Horsburgh K, Gallart-Palau X, Sze SK, Kalaria RN. Carotid Artery Disease in Post-Stroke Survivors and Effects of Enriched Environment on Stroke Pathology in a Mouse Model of Carotid Artery Stenosis. Neuropathol Appl Neurobiol. 2019 45(7):681-697. doi: 10.1111/nan.12550.
• Sigfridsson E, Marangoni M, Johnson JA, Hardingham GE, Fowler JH, Horsburgh K. Astrocyte-specific overexpression of Nrf2 protects against optic tract damage and behavioural alterations in a mouse model of cerebral hypoperfusion. Sci Rep. 2018 22;8(1):12552. doi: 10.1038/s41598-018-30675-4.
• Horsburgh K, et al. Small vessels, dementia and chronic diseases –molecular mechanisms and pathophysiology’ Clin Sci (Lond). 2018 132(8):851-868. doi: 10.1042/CS20171620.
• Manso Y, Holland PR, Kitamura A, Szymkowiak S, Duncombe J, Hennessy E, Searcy JL, Marangoni M, Randall AD, Brown JT, McColl BW, Horsburgh K. Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease. Glia. 2018 66(1):34-46. doi: 10.1002/glia.23190.
• Fowler JH, McQueen J, Holland PR, Manso Y, Marangoni M, Scott F, Chisholm E, Scannevin RH, Hardingham GE, Horsburgh K. Dimethyl fumarate improves white matter function following severe hypoperfusion: Involvement of microglia/macrophages and inflammatory mediators. J Cereb Blood Flow Metab. 2018 38(8):1354-1370.
• Salvadores N, Searcy JL, Holland PR, Horsburgh K. Chronic cerebral hypoperfusion alters amyloid-β peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice. Clin Sci (Lond). 2017 131(16):2109-2123. doi: 10.1042/CS20170962.
• Kitamura A, Sanz YM, Duncombe J, Searcy J, Koudelka J, Binnie B, Webster S, Lennen R, Jansen M, Marshall I, Ihara M, Kalaria RN, Horsburgh K. Long-term cilostazol treatment reduces gliovascular damage and memory in a mouse model of chronic cerebral hypoperfusion  Sci reports 2017 7(1):4299. doi: 10.1038/s41598-017-04082-0.
• Hase Y, Craggs L, Hase M, Stevenson W, Slade J, Lopez D, Mehta R, Chen A, Liang D, Oakley A, Ihara M, Horsburgh K, Kalaria RN. Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion. J Neuroinflammation. 2017 11;14(1):81. doi: 10.1186/s12974-017-0850-5.
• Hase Y, Craggs L, Hase M, Stevenson W, Slade J, Chen A, Liang D, Ennaceur A, Oakley A, Ihara M, Horsburgh K, Kalaria RN. The effects of environmental enrichment on white matter pathology in a mouse model of chronic cerebral hypoperfusion.  J Cereb Blood Flow Metab. 2017, 271678X17694904. doi: 10.1177/0271678X17694904.
• Duncombe J, Lennen RJ,  Jansen MA, Marshall I,  Wardlaw JM,  Horsburgh K Ageing causes prominent neurovascular dysfunction associated with loss of astrocytic contacts and gliosis. Neuropathology Applied Neurobiology 2017 43(6):477-491. doi: 10.1111/nan.12375. 

Information for students:

Willingness to discuss research projects with undergraduate and postgraduate students: YES - please click here