Dr. Montagne: As we age, there is a phenomenon called inflammaging, so it's a contraction of inflammation in aging. And there is several things happening as we age. There is what's called the seven pillars of aging, which basically has...there are seven things that overlap between normal aging and neurodegenerative diseases. And out of these seven, the central one is inflammation. So, as we age, we have more inflammation going on and we know that there is more cell adhesion molecules. So, these cell adhesion molecules start to be expressed at the endothelial, which is normally not there or in very minimal quantity, and we start having a significant amount of these cell adhesion molecules throughout the whole body.

And the brain is very sensitive to that because these cell adhesion molecules, what they do is they collect the immune cells from the brain...from the blood, sorry, to bring them into the brain. The more you have, the more inflammation...what we call neuroinflammation, the more inflammation you have in your brain. So, that's a normal aging process. And the fact that those endothelial cells turn into a proinflammatory phenotype, the pericytes that are right next to them will...so, there is a crossover. I won't go into details, but the pericytes will have to detach to let the immune cells go through. Physically, if the pericyte stays attached to the vessel, there is no possibility for the immune cells to go through and do their job. So, the fact that there is more inflammation of the vasculature as we age, there is more detachment...I would say physiological detachment of brain pericytes. That's one thing. And there is some report that as we age, there is less...we don't have the capability...I mean, the pericyte don't have the capability to reattach as we can do as we are young.

So, I don't know if that's clear, but at least there is some hint that tells us that the fact that the endothelial cells become more inflamed in a way, the vasculature is inflamed, the pericytes will react to that in a bad way. And so, they will start shortening their processes also. So, I didn't mention it but a pericyte, it's a small cell body with a process, like small processes, like an octopus kind of thing sitting on top of a vessel, and all these processes are here to push the blood flow, basically, and maintain the integrity. And these processes will shorten because of the inflammation, and of course, if the pericytes are shortening their processes, the flow will reduce.

And if it's a chronic thing, if we think about chronically having too much inflammation at the vasculature, the pericytes will chronically detach more and more and shortening their processes, so the leakage of the barrier will come at some point because the tight junctions and everything that makes the barrier intact will start to degrade over time and the flow will be drastically reduced. So, short answer, I'm speaking maybe a bit too much, inflammation of the blood vessels might be one trigger and that's something we can target therapeutically relatively easily by injecting drugs IV, right? Intravenously. So, that would be a perfect way of targeting the vessels to improve vascular function, hopefully.

Dr. Patrick: I think also, the fact that you're mentioning the role of inflammation being so critical and key in this process, kind of makes me think about lifestyle factors, of course, that aren't necessarily the same as therapeutically targeting with the drug. But omega-3 being one of...at the forefront of, one…omega-3 transport has been shown mechanistically, at least in animal studies, to regulate blood-brain barrier function through the Mfsd2a transporter. And it's also like many of the metabolites of both DHA and EPA, the marine omega-3 fatty acids, are involved in resolving inflammation. So, they have resolvins, they have the specialized pro-mediating molecules, the SPMs, and the maresins. And so, do you think there could ultimately be clinical relevance for omega-3 status in regulating dementia-associated, you know, blood-brain barrier leakiness, you know, in humans, or maybe something worth exploring?

Dr. Montagne: No, I cannot agree more, I think there is more and more studies coming up nowadays on omega-3. And you mentioned Mfsd2a, which is one of the markers we are studying carefully because it's specific to the smallest blood vessels in the brain, so the capillaries, and that's where most of the pericytes are. And there is a recent study that shows that as we age and with dementia, Mfsd2a, so the receptor for omega-3, it's reduced on the blood vessels. And there is also a link that where there is a reduction of Mfsd2a on blood vessels, that's where we see pericytes loss. So, we can almost connect what we were seeing earlier. Of course, these are just a few studies and it has to be confirmed.

But apparently, there's more inflammation of the blood vessels, to go back to the first question to link it, which, as we age also, Mfsd2a transporters and other transporters, not only this one but this one in particular, is decreased at the capillary bed. Which have an impact apparently on the pericyte function because we can see that this hotspot of Mfsd2a loss are also hotspots of pericyte loss, which means that where we have the leakiness of the barrier. So, yes, I cannot agree more, I think we have to study a bit more DHA omega-3 and how this impacts blood-brain barrier function because that could be some preventive interventions and things like that. Even like targetable with drugs, but yeah, I cannot agree more.