MICA: ET-1-mediated reduction of cerebral blood flow in Alzheimer's disease: therapeutic potential of zibotentan

Lead Research Organisation: University of Bristol
Department Name: Clinical Science at North Bristol

Abstract

Blood flow through the brain is reduced in patients with Alzheimer's disease (AD). The reduction occurs before the onset of dementia. In people who already have AD, the more marked the reduction in blood flow through the brain the more severe their dementia. Patients with AD do tend to develop structural changes to the blood vessels in the brain - degenerative small vessel disease (SVD) and cerebral amyloid angiopathy (CAA). However, the distribution of the reduction in cerebral blood flow differs from that of the structural changes to cerebral blood vessels in AD, and there is increasing evidence that it is largely mediated by functional rather than structural abnormalities of the vessels.

The brain damage and memory disturbances that occur in AD are thought to result from the accumulation of a substance known as amyloid beta (Abeta) in the brain. This occurs in two main forms, a shorter one (Abeta40) and a longer one (Abeta42). In AD there is an increase in the proportion of Abeta that is of the longer form (Abeta42). The longer form of Abeta causes nerve cells to produce more of an enzyme called ACE that, in turn, produces the chemical Ang II. In addition, both forms of Abeta increase the production of another chemical called endothelin-1 (ET-1): Abeta42 does so by acting on an enzyme (called ECE) that synthesizes ET-1 in nerve cells, and Abeta40 by stimulating the production of ET-1 in the lining of blood vessels in the brain. Both ET-1 and Ang II cause blood vessels to constrict, narrowing their lumen. This reduces blood flow through the brain in patients with AD, and thereby impairs the delivery of oxygen and nutrients to nerve cells and slows the removal of waste products, adversely affecting nerve cell function. In addition, experimental studies suggest that the reduction in blood supply may increase the production of Abeta and thereby accelerate the progression of the AD. In a rat model of AD, other researchers showed that injection of ET-1 led to more accumulation of Abeta, more marked secondary degenerative changes and impaired performance in memory tests.

ET-1 mediates its reduction in blood flow by acting on specific receptors in the vessel walls (ET-A receptors). Ang II mediates its effects by acting on other receptors (Ang II receptors). By blocking either or both sets of receptors, it should be possible to improve blood flow through the brain. We now wish to explore the utility of (i) zibotentan, a specific ET-A blocker produced by AstraZeneca, and (ii) losartan, a licensed Ang II receptor blocker, for improving blood flow through the brain in a rat model that combines ET-1-mediated reduction in blood flow and Abeta accumulation in the brain. The rat studies will allow us to examine the effects of zibotentan, losartan and a combination of the two in great detail, including how these drugs affect maintenance of flow when there are changes in blood pressure or brain activity, and what the effects are on Abeta metabolism (including on the activity of ECE and ACE, both of which help the brain to remove Abeta).

Both zibotentan and losartan are well tolerated when given over long periods of time to elderly people. These studies will clarify their separate and combined potential for restoring blood flow in AD - and potentially therefore improving memory and slowing the progression of dementia.

Technical Summary

Cerebral blood flow (CBF) is reduced in Alzheimer's disease (AD) before the onset of dementia. More severe reduction predicts more rapid cognitive decline. In mouse models the reduction in CBF greatly exceeds the decline in neuronal metabolic activity. The distribution differs from that of structural vessel disease and is probably mediated by functional vascular abnormalities.
AD is thought to be initiated by the intracerebral accumulation of amyloid beta (Abeta). We have shown that Abeta42 upregulates neuronal endothelin-converting enzyme (ECE)-2 and angiotensin-converting enzyme (ACE). ACE catalyses production of angiotensin II (Ang II) and ECE that of endothelin-1 (ET-1), both potent vasoconstrictors. ET-1 concentration is significantly elevated in AD cortex. In addition, Abeta40 increases ECE-1 activity in endothelial cells, and both ECE-1 activity and ET-1 level are elevated in blood vessels from AD brains; this is likely to contribute to impairment of functional hyperaemia in AD.

Cerebral vasoconstriction reduces CBF, impairs the delivery of oxygen and nutrients and slows the removal of waste products (including Abeta). Brain ischaemia also increases Abeta production. We and others reported the use of Ang II blockers (ARBs) to be associated with a reduced incidence of AD. No comparable human data are available for ET-1 receptor blockers. In a rat model of AD, injection of ET-1 exacerbated Abeta accumulation and neurodegeneration and impaired memory test performance.
We suggest that Abeta40- and Abeta42-mediated increases in ET-1 and/or ACE are at least partly responsible for reduced CBF in AD. ET-1 mediates its cerebrovascular effects through ET-A receptors. We propose to compare the effects of zibotentan, a specific ET-A blocker, and losartan, an ARB, on CBF, autoregulation, functional hyperaemia and other vasoregulatory pathways, in a rat model of Abeta-mediated cerebral vasoconstriction, with a view to zibotentan usage in AD.

Planned Impact

Any therapy that improves or even simply slows the decline in cognitive abilities and functional capacity in AD has the potential to have major impact not only on the well-being of individual patients (of whom there are about 0.5 million in the UK) but also family members and other carers, and on the cost of social care and healthcare delivery. AD is much the most common cause of dementia, which is estimated cost to cost the UK £23 billion each year. In the US, the current annual cost of caring for patients with AD is ~$200 billion and the value of unpaid care provided by family and friends is estimated at $210.5 billion, suggesting that the lost economic opportunity costs are similar to the direct costs. However, this is not solely a problem of affluent countries. Earlier this year the WHO issued a report citing the estimated worldwide cost of dementia in 2010 as $604 billion but noting that the worldwide prevalence of dementia (currently approximately 35.6 million) is estimated to reach 65.7 million by 2030 and 115.4 million by 2050, an increase that will disproportionately affect low and middle-income countries, placing a massive burden on their health and social systems and economies. Any treatment that even simply slows the rate of progression of AD in individual patients, that prolongs independence and delays the need for full-time care, will have a hugely positive impact on the social and economic burden of this disease.

Whilst we have learnt a great deal about the pathology and cellular biology of AD, the genetic and environmental factors that influence the risk of developing the disease, and how to diagnose it more accurately and earlier, that knowledge has not yet been translated into improvements in therapy. In this application we describe an approach that is novel, likely to be safe, already available for clinical use and, we believe, has a good chance of proving effective. It has the potential to be translated into clinical practice relatively rapidly, within the next few years. Innovative approaches to the treatment of AD are urgently needed and even if the results of this project prove disappointing, we suggest that the findings are likely to stimulate other research aimed at improving the CBF with a view to ensuring not only that neurons have an appropriate supply of oxygen, glucose and other nutrients, but also adequate haematogenous removal of potentially toxic products of neural metabolism.

Publications

10 25 50
 
Description Network development grants
Amount £227,253 (GBP)
Funding ID ARUK-NAS2016B-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 03/2019
 
Description Assessing the contribution of reduced cerebral oxygenation to cognitive impairment 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presentation at Alzheimer's Research UK Conference, March 19-20 2019, Harrogate
Year(s) Of Engagement Activity 2019
 
Description BDR3 Training Day, University of Bristol, November 2018 - Haemodynamics of Alzheimer's disease: what's bad for the brain is probably bad for the heart 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I participated in the raining day for nuerses and other members of staff involved in the Brains for Dementia Research project and as part of the training day gave this talk on our research.
Year(s) Of Engagement Activity 2018
 
Description Bristol Health Partners Dementia HIT, April 2018 - Vascular dysfunction and dementia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact This was an invited talk at the annual meeting of the Bristol Dementia Health Integration Team (HIT), an organisation that aims "to transform care for people affected by dementia through comprehensive research, integrating and improving care services and support, and by creating dementia-friendly communities".
Year(s) Of Engagement Activity 2018
 
Description Dementia: research using human brain tissue 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk at Neuroscience for Psychiatrists Update Day, University of Bristol, September 18, 2019
Year(s) Of Engagement Activity 2019
 
Description Invitation to present findings at the first Binational UK-Israel Neuroscience Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Will complete this section after the meeting.
Year(s) Of Engagement Activity 2014
 
Description Joint meeting of the Physiological Society, the Scandinavian and German Physiological Societies and FEPS, London - Europhysiology2018, September 2018 - invited talk 'Hypoperfusion, hypertension and Alzheimer's disease' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was an invited talk at the Joint meeting of the Physiological Society, the Scandinavian and German Physiological Societies and FEPS, London - Europhysiology2018, September 2018
Year(s) Of Engagement Activity 2018
 
Description Regulation of blood flow in dementia: a tale of misconception and misdirection 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Talk given at 61st London International Youth Science Forum, July 29 2019, Imperial College, London
Year(s) Of Engagement Activity 2019
URL https://www.liysf.org.uk/
 
Description Representing Alzheimer's: exploring Alzheimer's disease and other forms of dementia through films and science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "About 250 people gathered in the Great Hall at the University of Bristol on Wednesday March 20th to watch a series of short films about dementia and take part in a lively panel discussion of the issues raised.
The event was the brainchild of Bristol filmmaker James Murray-White, whose passionate commitment to fighting Alzheimer's disease stems from his own experience of caring for a loved one with the condition. James gave of his own time to curate seven short films and help to plan the evening, as well as sharing in the presentation of the material and discussion.
The films varied in style and content from documentary to drama and animation. One of them was James' own moving filmKeeping Mum, documenting his mother's battle with Alzheimer's over several years. Edinburgh director Christeen Winford, who travelled to Bristol especially for the occasion, contributed a powerful drama called Darkness in the Afternoon and a rough cut of Thinking Outside the Box, the latter being an interview with an artist who explains how having dementia has changed his perceptions.
After the films, Christeen Winford and James Murray-White joined Seth Love (Professor of Neuropathology, University of Bristol), Laura Palmer (Manager of the SW Dementia Brain Bank) and Mark Poarch (CEO of BRACE) to form a panel for open discussion. Some challenging and occasionally surprising questions were put to them and a fascinating discussion was the result."


The number of visitors to the South West Dementia Brain Bank (within the Dementia Research Group laboratories) has increased steadily over the past few years as word has spread of their interest and availability. These tours are hosted mainly by Candida Tasman and Laura Palmer but other members of the Research Group also help. We now host approximately two tours each week of groups of school children; students from a wide range of disciplines and ages; psychiatrists; mental health workers; nursing and care home workers; nurses; people who are interested in donating funds to dementia research via the Alumni Office or through charities; people who have registered to donate their brains to our brain bank after they pass away; and the relatives of brain donors. We have already had several further requests for visits since this public engagement event.
Year(s) Of Engagement Activity 2006,2013
 
Description Robert S Totten Lecture, University of Pittsburgh, October 2018 - Alzheimer's disease - cerebral hemodynamics, systemic consequences and therapeutic implications 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to be the Robert S Totten Visiting Professor, University of Pittsburgh and to give a talk (in October 2018) on my research into alterations in cerebral blood flow in Alzheimer's disease.
Year(s) Of Engagement Activity 2018
 
Description Seminar on 'Haemodynamics of Alzheimer's disease' December 2017 - University of Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I was invited to give a talk on our findings relating to changes in cerebral vascular function and hypertension in Alzheimer's disease
Year(s) Of Engagement Activity 2017
 
Description Visit by Lord-Lieutenant Mrs Peaches Golding OBE 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Professor Seth Love (SWDBB Director) and Dr Laura Palmer (SWDBB Manager) hosted Lord-Lieutenant Mrs Peaches Golding OBE on a tour of the South West Dementia Brain Bank and discussed progress in brain banking and dementia research in the UK, including studies in Bristol on the use vasoprotective agents in Alzheimer''s disease.
Year(s) Of Engagement Activity 2018
URL https://www.lordltbristol.org.uk/News-Events
 
Description XVIII International Congress of Neuropathology, Rio de Janeiro, September 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 400 people attended the International Congress of Neuropathology, at which I gave a plenary talk entitled 'Pathophysiology of disturbances in cerebral blood flow in dementia'

The talk generated a lot of interest and discussion.
Year(s) Of Engagement Activity 2014