BrightFocus Funds Encouraging Breakthrough for Future Alzheimer’s Treatment
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 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.