Dr. Roxana Carare speaks about the biological pathways involved in the accumulation of amyloid plaques, and why targeting these pathways could yield effective Alzheimer’s treatments.
Why does Alzheimer’s happen to some, but not others? We know that certain factors like genetics and lifestyle are at play, but sometimes dementia strikes even when you think you’ve done everything you could to prevent it. We spoke to Dr. Roxana Carare, M.D., Ph.D., professor of clinical neuroanatomy and experimental neuropathology in the University of Southampton, about how we may be able to clear the protein plaques in people who are developing Alzheimer’s, the new drugs coming out that may be able to stop its expansion across the brain, and how the most effective prevention might happen before birth.
- The brain has no lymphatic vessels like the rest of the body, so the drainage process fails, particularly after middle age
- Prevention starts in the womb. Animal studies have shown that baby mice from mothers with high-fat diets were not able to clear protein plaques, even though they had healthy diets
- A new drug under clinical trial in Japan may help clear the plaques
Being Patient: Why are you focused on the clearance of amyloid beta from the brain? Why is this important and what have you discovered?
Roxana Carare: In Alzheimer’s disease, as in other forms of dementia, there is an accumulation of waste products, not just amyloid; just different proteins, different products, either within the cells of the brain or in between the cells of the brain and that could also happen in the walls of the blood vessels.
In order to try and understand why this is happening, we have to look at how the brain is equipped for eliminating waste. We know that the brain does not have lymphatic vessels. Now, everywhere else in the body we have lymphatic vessels that eliminate fluid and waste products. For example, if you stand for long periods of time, your ankles swell up but you put your feet up, the fluid drains and your ankles regain their shape and function. There are no lymphatics in the brain, so automatically for one of the most active organs to not be equipped with the pipes that drain waste is a problem. However, we must eliminate waste somehow, and something happens from middle age onwards where this process fails.
What exactly are the pathways for eliminating waste from the brain? We know that amyloid is produced by the nerve cells and it’s then either broken down in the brain by various enzymes, taken up by various cells called macrophages or it crosses into the blood. But all of these systems fail with age. By careful examination of post-mortem material, we established that the amyloid is deposited in tiny channels called basement membranes. They’re about a millionth of the thickness of human hair. Now compare that with a large, one-half centimeter lymphatic vessel in the leg or in the lung. No wonder they fail in their function very early.
Being Patient: Are these blood vessels or are they different types of ducts that would be similar to a lymph vessel?
Roxana Carare: They are channels that are within the wall of a blood vessel. And weaved in between the muscle cells that constrict the blood vessel. If you imagine one of those red and white lollipops: the red is the smooth muscle of the artery; the white are the basement membranes. They are the drainage routes. The problem is they’re quite tortuous. They’re very narrow, so they’re prone to getting clogged up quite easily.
Being Patient: Do you think in someone who has Alzheimer’s or dementia, that that’s really where the problem is?
Roxana Carare: Yes, we’ve showed that, absolutely. And we’ve also shown that these channels change their composition and they fail in their function. They can’t eliminate waste when they’re old, so with increasing age, with possession of a certain genetic background called ApoE4, with lack of vitamin B and after immunization against amyloid beta. They simply get clogged up with the excess amyloid that you’re trying to eliminate by vaccination.
Being Patient: And why is it then, if they get less efficient with age, why is it that some people don’t develop dementia?
Roxana Carare: Some people, quite right, don’t develop dementia. What I think is happening is that there is a threshold, and in some people arteries will age in a more aggressive manner and they will become stiff and less able to pump out the amyloid along these channels. Whereas in other people the arteries are still maintaining a minimal level of elasticity, which brings me to prevention. The more you look after your arteries in young middle life, the more likely you are going to be able to preserve their function of not just pumping blood into the brain but pumping the waste out of the brain.
In Southampton, we have a very reputable research group on the maternal origins of adult disease. They’re looking at how the mother’s diet during pregnancy and lactation influences the health of the developing embryo and baby. We looked at some of the brains of baby mice from mothers deliberately fed a high-fat diet during pregnancy and lactation. After birth, the baby mouse was on a normal diet, and yet their brains were not able to clear amyloid. What that tells us is that the integrity of the blood vessels is key to be able to eliminate waste along these channels.
Being Patient: I think that adds to a lot of research that’s coming out that says what’s good for your heart is good for your brain. In terms of prevention, we’ve come up with a lot of things that you can do that we know are good for your heart. If we’re looking for treatments for someone who has developed Alzheimer’s, has your research pointed you in any directions?
Roxana Carare: Yes. If you search for a treatment, you have to search for the target that will influence that process. This is an active process by which waste is eliminated along these narrow tortuous channels. The motive force for that is provided by the contraction of the smooth muscle cells, so as a muscle cell contracts and relaxes it will essentially pump the channel next to it. We’ve already shown that if you act upon the innervation, the nerve supply of those muscle cells, then you can actually influence this process. There is a drug called Cilotizol that is under clinical trial in Japan and we’ve already demonstrated it improves the clearance.
Then there’s another drug target that appears to influence the chaperoning of amyloid beta. It’s also all about how soluble the amyloid beta is: Can we move it about? Can we pump it out a little bit with more ease? We think that a compound called chlosterin that also is involved in transporting the good cholesterol around the body might be helping this process. I’m working with John Fryer in the Mayo Clinic and we’re looking to see how chlosterin can improve this process. Compounds such as chlosterin that chaperone amyloid beta with a little bit more ease may have a better chance in later stages where we’re looking more at basically pushing amyloid beta out by its solubility and altering its state rather than the contraction of the smooth muscle cells. So even in a stiff, really old artery, really affected by disease, this maybe could have a chance. Until we do those experiments and until we provide the data, we won’t be able to know with certainty.
Being Patient: And it sounds like you’re saying that prevention is almost better than treatment?
Roxana Carare: Absolutely I’m saying that. And actually, prevention even before birth so the mother’s responsibility starts from pregnancy, really.
This interview has been edited for clarity and length.