Prof. Roxana Carare on how the build-up of plaque in the brain could be the key to Alzheimer’s research

Roxana Carare is a medically qualified Professor of Clinical Neuroanatomy and experimental neuropathology at the University of Southampton.  Roxana leads interdisciplinary, international research on neuroanatomy and neuropathology, demonstrating the unique lymphatic drainage pathways by which fluid and soluble amyloid are eliminated from the brain along basement membranes within the walls of cerebral capillaries and arteries (Intramural Periarterial Drainage Pathways, IPAD). She currently leads Carare Group, with Professor Roy O. Weller as group mentor, at the University of Southampton.

You’ve had quite the journey to Clinical Neuroanatomy. Can you tell us what you studied and how you ended up here?

I studied Medicine in Bucharest, Romania, with many of the clinical attachments undertaken in Dublin. During my studies I developed a love for Anatomy and started teaching part-time. In October 1998 I started a job in Anatomy at the University of Southampton, with the initial aim of teaching Anatomy while preparing for clinical examinations. During my appointment I became fascinated by the lack of traditional lymphatic vessels in the brain. Lymphatic vessels are tubes by which waste produced by different organs are removed into the blood. Through teaching I met the person who became my mentor and PhD supervisor in a project that aimed to determine the lymphatic drainage pathways for waste produced by the brain. The failure of these pathways to eliminate waste efficiently results in sticky plaques in the walls of blood vessels and in Alzheimer’s disease. Analysing these lymphatic drainage pathways in the brain and harnessing them to prevent the accumulation of waste/sticky plaques in the brain has been my focus for the last 20 years.

How are Alzheimer’s and lymphatic draining linked? You propose that the brain’s inability to get rid of waste is linked to diseases like Alzheimer’s. What stops the brain from being able to do this?

There are no traditional lymphatic vessels in the brain. Instead, soluble proteins are eliminated along tiny channels that are of the thickness of 50-100 nm, spiraling around smooth muscle cells (Intramural Periarterial Drainage – IPAD). Pathways present in the walls of arteries in the brain and carry waste from the depth of the brain to the surface, against the direction of blood and pulse flow. These pathways can become compromised with increasing age, the APOE4 genotype, mid-life high blood pressure, or mid-life high cholesterol. The drainage of soluble proteins then fails, leading to a build up of sticky plaques in the walls of arteries. This in turn leads to low blood supply and frequent bleeding. The nerve cells are deprived of efficient blood supply and die, causing dementia, in particular Alzheimer’s disease.

There have been Alzheimer’s vaccine trials that have so far failed. Why is this?

The trial vaccines involved targeting the sticky plaque, breaking it down, and then releasing toxic material. Imagine having your dustbin emptied by the local council every week directly in front of your home – it doesn’t make sense and isn’t particularly efficient. A similar process happened in immunisation – the trials started late (in the disease lifecycle), when there was a lot of existing build up in the brain. Then lots of soluble toxic material was released that had nowhere to drain, because the pathways for drainage were already compromised.

Is Alzheimer’s treatable by prevention? And what are the steps to prevention?

Prevention strategies would be much more efficient because the build up of plaque begins 20 years before the symptoms – in other words, by the time symptoms are detected, it is too late and dangerous to be interfering with the plaque.

The major risk factors for dementia are almost identical to those for heart disease. Therefore it is logical to state that preventing cardiovascular problems may also prevent dementia. However, conducting a trial around this would be particularly difficult, as it would mean following up with people over decades and relying on compliance to diet, etc.

“Prevention strategies would be much more efficient because […] by the time symptoms are detected, it is too late and dangerous to be interfering with the plaque.” 

What is the aim of your current EPSRC funded project? , “What is the answer to effective draining”? Can you tell us what you’re hoping to demonstrate?

We’re collaborating with mathematicians and physicists and have demonstrated that the force generated by the contraction of the smooth muscle cells in the walls of arteries in the brain is sufficient for efficient drainage.

What could be prescribed to patients to facilitate the elimination of waste?

There are two categories of compounds (medication) with which we are hoping demonstrate improved drainage (IPAD): 1) compounds that act upon the receptors/innervation of smooth muscle cells to increase their force of contraction in the face of arteriosclerosis (thickening of the artery walls); 2) compounds that can chaperone the drainage of waste.

“The trial vaccines involved targeting the sticky plaque, breaking it down, and then releasing toxic material. Imagine having your dustbin emptied by the local council every week directly in front of your home – it doesn’t make sense and isn’t particularly efficient.”

It’s widely recognised that Alzheimer’s has a higher occurrence in women than men – is there any indication why this is the case?

In women’s bodies, the biology of female specific hormones such as estrogen interacts closely with the biology of fats. We know there is a strong link between high cholesterol and risk of developing Alzheimer’s disease. There are studies that suggest that the female hormones (estrogen) increase the “bad” fats/cholesterol in the blood. Of course, there are many factors that lead to high cholesterol and a good diet and exercise helps to prevent this occurring. This means that women need to work harder through dietary interventions and exercise to prevent Alzheimer’s disease.

You mentioned that it took you 5 years to do your PhD as you were also raising children. How did you manage this?

The environment in my institution was extremely supportive and our Faculty now has one of the most attractive schemes for maternity leave. I was fortunate to have an extremely supportive mentor, PhD supervisors that completely accepted and encouraged flexibility and the vast majority of my colleagues were very helpful.

What kind of advice would you offer to someone who may be in a similar situation (i.e. a parent with childcare duties who is also working towards their PhD)?

Ask for assistance from line managers and colleagues – sometimes people may not offer it if they don’t want to appear to be interfering. If the PhD supervisors are supportive, they should allow flexibility and recognise that it may take longer, but the levels of motivation are extremely high if someone with childcare or any other form of care duties is happy to proceed to take on this extra challenge.

Could you tell us about the Southampton University Faculty for Medicine’s sessions for staff?

Our wellbeing sessions for staff are of huge impact, aiming to resolve and prevent any issues that come up. The sessions are regular, run by the same councilor, allowing people to develop trust through familiarity. The sessions address common issues that can rapidly escalate and affect wellbeing and work: anxiety, stress, bullying. Southampton has also formed a partnership with the University of Newcastle to create a national bank of mentors that can address varied issues, such as gender, to race, intersectionality, disability etc. More mentors should mean that more people have access to advice and support, without overburdening potential mentors. It would also allow exchange of good practice.

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