Drawing toxic Aβ out of the brain
“Inject the antibodies into the blood; the blood then becomes a sponge for the amyloid beta (Aβ); then you open up the barrier very marginally and allow the Aβ to get soaked into the sponge. It’s classic osmosis by diffusion, just like those classic experiments we learned in school,” says Alzheimer’s researcher Matthew Campbell, PhD.
In an interview, below, Campbell describes his exciting work to draw toxic Aβ out of the brain, which has been successful in mouse models of Alzheimer’s.
Campbell and his team are regulating the blood-brain barrier in tandem with antibodies already developed that bind to Aβ. The technique is envisioned as a way to protect the brain in early Alzheimer’s. The project is funded by the BrightFocus Alzheimer’s Disease Research program.
A BrightFocus-funded research team has discovered a potentially new way to get Alzheimer’s medications into the brain, an encouraging breakthrough on a notoriously difficult medical challenge.
This new research, reported in the September 18 issue of Science Advances and led by BrightFocus grantee Matthew Campbell, PhD, of Trinity College Dublin, represents a potential new way to help clear the brain of a build-up of the toxic amyloid beta (Aβ) that leads to Alzheimer’s.
Unlike other parts of the body’s circulation, where nutrients and waste pass in and out of vessel membranes, the brain’s circulation is tightly controlled to keep out damaging substances, such as harmful chemicals and infections. This is often referred to as the blood-brain barrier (BBB). To accomplish this, blood vessels in the brain have with extra-strong seals, called tight junctions, between the cells lining the inside of capillaries. These seals are maintained by enzymes known as “tight junction proteins.” It is as if the cells lining capillaries are glued together and only the smallest molecules, sodium and potassium ions, can travel in and out.
The brain’s levels of peptides rise steadily in the decades leading up to Alzheimer’s disease (AD), and the accumulation of toxic Aβ fragments that are prone to clumping together and creating plaques is a major factor in Alzheimer’s onset. When the brain can no longer rid itself of excessive Aβ, neuron-killing plaques and tangles gradually start to develop. The brain’s ability to clear Aβ is influenced by factors like genetics and oxidative stress that comes with exposure and age.
Researchers are now focusing on getting that excess Aβ out of the brain before it creates problems; however, because of the BBB, it’s not possible to send medications through the bloodstream to do so. Instead, most strategies have focused on arranging “transport,” ie, coaxing another substance recognized by the brain’s immune system to give a medication a piggy-back ride in, so it can remove Aβ. Much work has centered around the use of antibodies, which are manufactured live cells that bond to Aβ and tau, to act like sponges to soak up these unwanted particles, which are then engulfed and removed by other waste-clearing cells in the brain.
The novel ground that Campbell and his team are exploring is the paracellular movement of Aβ through the BBB. “Paracellular” refers to the movement, or diffusion of these substances, through the space between cells. In experiments involving autopsied AD brains and live mice models, they suppressed the tight junction proteins claudin-5 and occludin, and found that led to higher circulating levels of Aβ traveling through the BBB and into the bloodstream. In live mice models, this improved Aβ clearance was associated with the mice performing significantly better on a maze designed to test cognitive function (eg, hippocampal spatial memory). In still another experiment, the researchers also found that circulating soluble Aβ temporarily allows for clearance across the BBB.
Importantly, to suppress claudin-5 and occludin, the Trinity researchers used an agent that has already entered clinical trials for other purposes, and is thus already is being tested for safety. Future research may lead to human use, and one day, by modulating tight junctions in this fashion, a cocktail of oral agents could be absorbed and delivered through the bloodstream to the brain to treat AD. It’s an approach that has helped bring the HIV/AIDS epidemic under control.
A Mind-Sight Connection
Campbell, who heads this investigation, is building an exciting bridge between research on diseases of mind and sight. His current work on Alzheimer’s is supported by BrightFocus’s Alzheimer’s Disease Research (ADR) program, while his ground breaking work in vision diseases was funded through BrightFocus’ Macular Degeneration Research program. “It’s great to be working in the Alzheimer’s field,” Campbell said.
In a statement and video released by TCD, he summarizes his latest breakthrough. “Our recent findings have highlighted the importance of understanding diseases at the molecular level,” Campbell said. “The concept of periodic clearance of brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer’s patients in the future. The next steps are to consider how this might be achieved.
Campbell’s new Alzheimer’s research is already being widely discussed in the field, and appears poised to drive further advances to finding effective treatments and cures for the disease.
In an interview, he talked about some of the parallels between disease of mind and sight, including the difficulty in administering treatments (in the eye’s circulation there’s a barrier much like the BBB) and in both diseases, there’s a protein buildup that ultimately leads to nerve loss.
In a statement released by TCD, he summarized his latest breakthrough. “Our recent findings have highlighted the importance of understanding diseases at the molecular level,” Campbell said. “The concept of periodic clearance of brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer’s patients in the future. The next steps are to consider how this might be achieved.
Interview with Matthew Campbell, PhD
Can you describe these tight junctions?
MC: Tight junctions are the points of contact between endothelial cells that line the inside of blood vessels. They're made up of a series of interacting proteins, and they essentially "glue" the cells together. Lots of endothelial cells throughout our body have tight junctions, but the blood vessels in our brains and our retinas have the most elaborate ones. They prevent the entry into the brain of bacteria, viruses, and blood-derived toxins.
From an evolutionary standpoint why did they develop?
MC: Your brain needs a massive blood supply to meet its energy needs. It consumes about 25 percent of the energy that you take in; so, if you eat a sandwich, a quarter of the energy in it is likely used by your brain. The problem with this large blood supply is that if viruses and bacteria gain access to your brain, the brain has no process to deal with that. Unlike other parts of the body, which can mount an inflammation mediated defense, if the brain starts swelling, there’s nowhere for it to go; it’s bound in by the skull. Thus, as an immune privileged site, evolution has given us a blood-brain barrier (BBB) held together by these tight junctions that essentially seal the gap between contacting endothelial cells to "zero." Only the tiniest of material can squeeze through.
What led you to make a connection between this and Alzheimer’s disease?
MC: If you look at the brain of somebody who’s died from Alzheimer’s, and stain it for tight-junction proteins, you see patchy staining , but not in the same areas where there are plaques. Around plaques, there’s very little tight junction protein, but if you move away from the plaques, there’s lots.
So [from this] we knew there’s a BBB component in Alzheimer’s and we also discovered that as tight junction protein levels change, and as junctions open up, the amyloid beta (Aβ) comes flooding out of the brain.
Is that a major contributor to Alzheimer’s?
MC: Yes. We think Alzheimer’s disease is essentially a disease of aberrant clearance. As clearance mechanisms slows down with age, amyloid, and plaques build up in the brain. It’s similar to the build-up of drusen in AMD, which is almost certainly a disease of aberrant clearance.
If you could regulate these tight junctions, and get them to open up using drugs, then you could potentially allow the Aβ to diffuse out of the brain. It could be a therapeutic approach. That’s what we’re working towards with our BrightFocus grant.
Has this problem of the BBB delayed Alzheimer’s treatments—and do you see this changing?
MC: It has delayed pharmacological development for all brain disorders, not just for Alzheimer’s. Drugs that get into the brain have to be small and lipophilic. So, a common drug like lithium, that's used for neuropsychiatric disorders, is very small and can easily get across the BBB. But anti- Aβ drugs that are in development for AD are orders of magnitude bigger.
We’re using the approach of regulating tight junctions in tandem with antibodies that have already been developed, to try and draw the Aβ out. So basically: make the antibodies like a sponge; inject the antibodies into the blood; the blood then becomes a sponge for the Aβ; then you open up the barrier very marginally and allow the Aβ to get soaked into the sponge. It’s osmosis by diffusion, just like those classic experiments we learned in school. If you have an area of low sugar, and an area of high sugar, the high sugar will diffuse into the low sugar. It’s the same with Aβ. It can passively diffuse out of the brain if you can marginally open up these junctions.
And what are your results so far?
MC: Working with a mouse model of Alzheimer’s, we’ve taken mice at a very young age, pre-symptomatically; injected them with drugs that open up the barrier transiently; and followed the same mice for one year. At the end of that year, the mice have better cognitive function, they’ve got better memory, and they’ve got higher levels of Aβ in their circulation, which means that it’s coming out of the brain. So there’s proof of efficacy [in the mouse model].
Alzheimer’s is thought to begin 10-20 years before symptoms occur. What stage would this treatment be directed towards? How early in Alzheimer’s course?
MC: Getting in as early as possible is the only way to treat Alzheimer’s as effectively as possible. It’s a neurodegenerative condition that shrinks the brain irreversibly. End-stage Alzheimer’s is essentially untreatable; you’re treating a brain that has diminished to the same size as a one-year-olds brain. The cells that allow you to store memories are dead. You can’t make the cells grow again, and if they do grow, they’re not going to store the memories that they held 20-30 years ago.
So it won’t work in patients with advanced Alzheimer’s. We need to get to patients early, and even then the clinical readout and endpoints [ie, the trial results] will take a long time, 2-3 years. It’s easier to evaluate therapies in the eye, because you can see the results. Blood vessels stop being leaky; cells stop dying, vision stabilizes or improves. But with Alzheimer’s, unless you can get these vulnerable people to an [imaging] center, you can’t see whether a therapy is working or not.
Isn’t it going to be hard to recruit people at preclinical stages?
MC: That’s the essential problem with all Alzheimer’s clinical trials, and we’re going to face the same challenges. We can detect amyloid years before symptoms develop, but if you were told that you’re going to develop Alzheimer’s in 20 years’ time, would you put yourself into a clinical trial? When you’re completely asymptomatic and have no family history?
Who are your collaborators, and what are your next steps on the project?
MC: It’s all mice at the moment, but we will be extending our research to the non-human primate model. James Keaney [first author] was a PhD student in my lab and has stayed on as a post-doc. He's about to start a prestigious William Harvey International Translational Research (WHRI) fellowship between my lab here in TCD and Prof Sean Callanan's lab at Ross University in St Kitts, and we have an active collaboration with a primate facility on the island, so that will be an exciting next step.
The second author on the paper, Dominic Walsh, is based in Harvard and is an international authority on Aβ biochemistry. He worked in Dublin for many years, hence the collaboration. In addition, we are also very fortunate to work with Prof Michael Farrell, a neuropathologist at Beaumont Hospital who established the Dublin Brain Bank which provides neuroscience tissues for our work.
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