07 Oct 21. UK DRI Edinburgh: BBB in dementia

“The great wall: targeting the blood-brain barrier in dementia” – find out how the UK DRI at Edinburgh is driving this research area.

Year by year, our knowledge of the fundamental biology behind dementia is improving & with it, progress made on promising new therapeutics. What has become most evident is the need to target the earliest stages of diseases like Alzheimer’s, to maximise impact & save as much of the brain as possible. A growing area of interest is the specialised blood vessel network surrounding the brain, the blood-brain barrier (BBB), whose dysfunction & breakdown is thought to be one of the initial events in several neurodegenerative diseases.

To build a better understanding & explore opportunities for treatments in this area, Director at the UK DRI’s Centre at the University of Edinburgh, Prof Giles Hardingham is taking an integrated approach, bringing together specialist researchers & clinicians, & answering major questions at the intersection between our nervous, vascular & immune systems.

The BBB, like vasculature in the rest of the body, contains a layer of endothelial cells which line the inner tube of the vessels. However, due in part to ‘tight junctions’ between these cells, the BBB is extremely selective to maintain an optimised microenvironment needed for brain function. The specialisation continues with input from multiple other cell types: pericytes which regulate blood flow; neurons that send electrical messages across the brain; astrocytes that connect blood vessels & neurons to maintain metabolism; & microglia which are the resident brain immune cells. Together these cells serve a vital collective role in protecting the brain while helping it function correctly. As Dr Blanca Díaz-Castro, an expert on astrocyte biology, explains, there are still many challenges that remain in the field.

“There are fundamental questions that we need to answer in respect to the BBB. How is the integrity of the BBB maintained? How do BBB cells interact with each other? & what molecular pathways become dysfunctional in the earliest stages of disease? I believe that solving these will provide successful avenues for early diagnosis & treatment of dementia.”

Modelling the BBB

One of the first obstacles is the development of cellular models that accurately mimic the brain & surrounding vasculature. The lab of Prof Hardingham is pioneering innovative new platforms, bringing together the multiple cell types to study them outside of the body. By using cell types from different species in the platform, the team, aided by a computer programme, are able to use small differences in DNA sequence to easily identify & separate the effects without needing to physically sort the cells.

“What we’ve discovered so far is that the interactions between cells are so important to brain health. For example, microglia need both neurons & astrocytes to maintain a healthy shape & expression of genes,” explained Prof Hardingham. “This knowledge is not only helping us build accurate research models, but also in investigating disease causes. The loss of cellular communication could result in the dysregulation that we see in advanced ageing or in disorders like Alzheimer’s.”

With funding from the Dementia Discovery Fund, Prof Hardingham & colleagues have successfully constructed a cellular model that exhibits key characteristics of the BBB including transport of molecules & impermeability to drug molecules. The platform can now be exploited to solve some of these fundamental challenges involving the BBB in health & disease, which will hopefully lead to the development of new therapeutics.

A new avenue for dementia therapies

As we age or begin to develop diseases like Alzheimer’s, there’s evidence that the BBB’s selective permeability begins to deteriorate. This leads to dysfunctional exchange or ‘crosstalk’ between the brain & the rest of the body which can lead to several complications. Perhaps most damaging is the increased influx of inflammatory mediators from the blood, stoking neuroinflammation in the brain, & perhaps driving neurodegeneration.

Related to this loss of integrity in the BBB is the dysfunction of endothelial cells that usually pack close together & form the first layer of blood vessels. This could be caused by a reduction in the number of tight junctions between the cells. The phenomenon is being investigated in cerebral small vessel disease (SVD), a condition that affects blood vessels of the brain & is a major risk factor for the development of dementia. One of the researchers at the forefront of this field is clinical vascular scientist, Prof Joanna Wardlaw CBE.

Prof Wardlaw is leading a trial (LACI-2) in people who have experienced a type of stroke often caused by damaged small blood vessels in the brain, known as a lacunar stroke. Since the endothelium is known to be damaged in small vessel disease resulting in subtle increased leakiness & damage to the brain, the team are testing the effect of two existing drugs for their endothelial cell stabilisation & support properties - cilostazol & isosorbide mononitrate currently used for other circulatory diseases. They are monitoring the effects on patient clinical outcomes including cognition & on small vessel brain damage using MR. “If the results are encouraging, then we plan a larger trial to find new effective ways to treat small vessel disease including lacunar strokes & vascular cognitive impairment & potentially prevent some cases of dementia,” said Prof Wardlaw.

Another area of interest & possible utility for in vitro models, is in the investigation of inflammatory signalling across the BBB. When we experience an infection, the significant immune response generated impacts our brain through various routes, one of which being specific transporters & channels present in endothelial cells. The result of this can be delirium, a rapid onset but usually acute set of symptoms associated with problems thinking, focusing & memory. Although these effects usually subside as the infection is resolved, there is evidence that delirium significantly increases the risk of dementia. This would fit with our growing understanding that neuroinflammation can drive neurodegenerative processes in disease. Therefore, developing treatments to reduce this signalling across the BBB may be beneficial. This area is of particular interest at this time, as we see worrying neurological effects caused by Covid-19 infection.

Helping drugs into the brain

Successfully targeting a disease mechanism is a huge achievement with the next critical step being the delivery of drugs to the right sites & cells. This is by no means a straightforward task because, as with bacteria & viruses, the BBB is very effective at preventing the entry of drug molecules developed to treat brain disorders. Prof Hardingham explains.

“In the case of some antibody treatments for brain disorders, only 0.1-1% of the drug enters the brain & where it needs to be,” explains Prof Hardingham. “That may be enough for a clinical effect in some cases but moving more drug across the BBB will allow us to lower doses, avoiding potential side effects. There are multiple approaches currently being tested but no major breakthroughs or universal platforms as of yet. This is a critical obstacle we must overcome in neurodegenerative disease therapy.”

The brain delivery methods largely fall into two categories: invasive & non-invasive. Some invasive technologies have been around for a while, such as direct injection into the cerebrospinal fluid or brain, but these are not appropriate for rollout to the wider population. Greater hope lies in the many innovative non-invasive approaches being trialled including the use of focused ultrasound to oscillate bubbles & physically open the BBB, nanoparticle systems which wrap the drug in a package capable of crossing the barrier & developments which exploit endogenous cellular transport systems such as a receptor for insulin. Dr Axel Montagne, a specialist in pericyte biology, comments on one of the more controversial topics surrounding the study of the BBB & drug delivery.

“You may assume that if the BBB had lost its integrity or become broken, it would be easier for drugs to enter the brain - some researchers are even trying to exploit this further with techniques such as ultrasound. However, I am cautious about this approach & long-term consequences of opening the BBB. I believe the key to improving diseases such as Alzheimer’s, is to repair the BBB, so it can clear the brain of protein aggregates through functional waste pathways. Better drug design & utilising transport systems will help with drug delivery across the BBB & into the brain.”

Although a number of these delivery methods look promising, they all have strengths & weaknesses, & gaining greater knowledge through these new models, will help establish successful technologies that make their way to the clinic.

On his ambitions for the UK DRI at Edinburgh Centre, which now has 12 Group Leaders, Prof Hardingham explains why the approach & strategy is laying the foundations for future treatments.

“With what we now know about the complexity underlying the diseases that cause dementia, we must start to bring together different research fields & integrate our knowledge. That’s what I’m hoping to achieve with the UK DRI Edinburgh Centre, recruiting brilliant discovery researchers & harnessing the very best clinical expertise & experience.

The foundation of success in therapeutics is good understanding of the fundamental biology & mechanisms. Not only will this help us in delivering drugs into the brain, through the development of better models for instance, but I’m also a strong believer that the dysfunction at the BBB is a key early step in multiple brain disorders & provides a promising avenue for treatments.”

This news item is republished from the UK DRI article, please view this here.