Long-term reduction in blood flow - a cause of vascular dementia and Alzheimer's disease?

Research project: Vulnerability of the neurovascular unit to cerebral hypoperfusion: An early event in vascular dementia and Alzheimer's disease? 

Lead Investigator: Prof Karen Horsburgh

Institution: University of Edinburgh

Grant type: Project

Start Date: July 2012

Completion Date: October 2015

Amount: £335,176

What was the project, and what did the researchers do?

The flow of blood to the brain delivers oxygen and nutrients to brain cells and this process is essential for the cells to function and for normal thinking, learning, and memory.  In vascular dementia and Alzheimer's disease the flow of blood to the brain is thought to be reduced very early on in disease progression due to aspects such as high blood pressure or a thickening of the blood vessels (called atherosclerosis). Reduced blood-flow in people with vascular dementia and Alzheimer's disease may potentially lead to damage to brain cells and cognitive decline. 

In this study, the researchers studied a particular part of the brain called the neurovascular unit. This is a highly coordinated system of blood vessels and brain cells which helps to control blood supply to the brain. Prof Horsburgh's team reduced the flow of blood through this part of the brain in mice.  They hoped to understand how long-term reduced blood flow to this part of the brain affects its ability to function. They also looked for the effect of low blood flow on other changes in the brain associated with Alzheimer's disease and vascular dementia, particularly build-up of amyloid protein. 

The researchers were aiming to gain insights into which changes in blood flow to the brain lead to vascular dementia and Alzheimer's disease and why. 

What were the key results, and how will this help in the fight against dementia? 

Mice that experienced reduced blood flow in the neurovascular unit experienced a quick decrease in memory abilities. After several months of reduced blood flow, there were changes to the structures of the cells of the unit, some of which suggested that the unit was damaged. This result suggests that a reduction in blood flow damages the blood control unit and prevents brain cells from receiving the oxygen and nutrients they need. This may have an effect on memory.

The researchers also measured other markers for vascular dementia and Alzheimer's in the mice. For example, they found that reduced blood flow was associated with an increase in the Alzheimer's hallmark amyloid protein. When the brain was exposed to low blood-flow for a long time, this increased the build-up of amyloid.

This study provided evidence that reduced blood flow to the brain may be an important part of the early stages of vascular dementia and Alzheimer's. It highlights the possible role of the neurovascular unit in the mechanism behind this association. This unit could be a target for therapies and treatments in the future.

What happened next? Future work and additional grants

Prof Horsburgh is leading one of our specialist Doctoral Training Centres in order to further understand the role of blood flow to the brain in Alzheimer’s disease and vascular dementia. She is also applying for funding to study the ways that low blood flow affects the neurovascular unit in more depth.

How were people told about the results? Conferences and publications

Publications:

Holland PR, Searcy JL, Salvadores N, Scullion G, Chen G, Lawson G, Scott F, Bastin ME, Ihara M, Kalaria R, Wood ER, Smith C, Wardlaw JM, Horsburgh K. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J Cereb Blood Flow Metab. 2015. 35(6):1005-14 doi: 10.1038/jcbfm.2015.12. 

Searcy JL,, Le Bihan T, Salvadores N, McCulloch J,  Horsburgh K. (2014) Impact of age on the cerebrovascular proteomes of wild-type and Tg-SwDI mice. Plos One 9(2):e89970. doi: 10.1371/journal.pone.0089970.

Aiqing Chen, Rufus O. Akinyemi,* Yoshiki Hase,* Michael J. Firbank, Michael N. Ndung’u, Vincent Foster, Lucy J. L. Craggs, Kazuo Washida, Yoko Okamoto, Alan J. Thomas, Tuomo M. Polvikoski, Louise M. Allan, Arthur E. Oakley, John T. O’Brien, Karen Horsburgh, Masafumi Ihara, Raj N. Kalaria† 

Frontal White Matter Hyperintensities, Clasmatodendrosis and Gliovascular Abnormalities in Ageing and Post-stroke Dementia Brain (accepted)

Manuscripts in preparation:

Sustained mild chronic hypoperfusion promotes the accumulation of cerebral amyloid angiopathy and  microinfarcts in TgSWDI mice. Natalia Salvadores, James L. Searcy, Jessica Duncombe, Fiona Scott,  Philip R. Holland, and Karen Horsburgh 

Ageing causes neurovascular dysfunction associated with  loss of  astrocytic contacts and inflammation independent of cerebral amyloid deposition. Jessica Duncombe, Ross Lennen, Maurits Jansen, Ian Marshall, Joanna M. Wardlaw, Karen Horsburgh 

Cilostazol ameliorates working memory and white matter function in a mouse model of moderate chronic cerebral hypoperfusion. Yasmina Mano-Sanz,  Akihiro Kitamura. James L. Searcy, Jessica Duncombe, Juraj Koudelka, Scott Webster, Masafumi Ihara, Raj Kalaria,  Karen Horsburgh

Other dissemination activities

Invited debate leader at Vas-Cog (Lille), 2011

An animal model of small vessel disease Stroke Research Group Seminar Series, (University of Edinburgh), 2011

Invited external speaker at Cardiovascular symposium day, 2012

Human cerebral small vessel disease: insight from experimental models, 2012

Invited conference speaker EuropeanCongressNeuropathology12 (ECNP12), 2012

A mouse model of chronic cerebral hypoperfusion to study mechanisms leading to white matter damage, 2012

Organiser and chair at Public Lecture on ‘Dementia Awareness’ University of Edinburgh (advertised in local papers and various dementia groups and related web pages), 2013

Invited speaker at ARUK conference (London) 'The link between Vascular disease and Alzheimer’s disease : insight from a mouse model of chronic cerebral hypoperfusion', 2015

Symposium Organiser and speaker at BNA conference (Edinburgh) 'Metabolic and vascular contributors to dementia', 2015

Organiser of satellite dementia conference for ARUK network (Edinburgh), 2015

Invited speaker at MRC DPUK meeting (London), 2015

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