Understanding the Blood-Brain Barrier and Its Link to Aging and Disease | LiveTalk | Being Patient

okay hi everyone welcome to being patient brain talks i'm deborah khan founder of being patient we are going to talk about the blood brain barrier did i get that right the three i always mix up those words um we are going to talk about how this barrier which um surrounds our brain in and allows things to go in or um is is a very protective protective shield of our brains how it changes as we age and i'm really excited to have with us daniella copper some of you may remember her because we had spoken in the past about her extensive research on stress and how that impacts the brain so today we're going to talk about the brain blood barrier um thank you so much daniela for joining us and it's great to see you again thanks debra for inviting me again very exciting to be with you okay let's start just for first uh let's start by giving people an understanding about this barrier and really what it means for our brains i always picture it as the thing that's keeping our brain together but it's a very um is it fair to say it's a protective back barrier yeah so i think the name itself is very misleading right it's i get two things one is people describe it as you did sort of a some membrane or balloon around the brain which they exist there's three of those meninges but that's not the blood-run barrier at all so there are protective um membranes around the brain three of them and that's not it and then other people say sometimes like it's probably something here like a gate and that's not it as well so what it is is it's in the wall of the blood vessels and the small blood vessels and the capillaries and your brain is very very full of blood vessels it's actually um you know a majority of oxygen in in glucose consumption in the body especially per weight goes to the brain so it's very rich in blood vessels and the blood vessels around them have a cellular and molecular elements that act like a filtration system so if you think about it it's like liquid that has extra filters around so in the rest of our body when blood flows we actually have a lot of exchange with the tissue around it from the blood vessel but here there's filtration that protects so things don't just go in so cells for example don't go in means if you think if you get a cut in your finger or anywhere um in your body there will be a rush of immune cells to that area but because of the blood-brain barrier immune cells cannot cross just readily into the brain tissue for example so it's protected from cells and it's protected from toxins and blood molecules endogenous blood molecules as well okay and this is obviously um part of our brain that um um so where why is it relevant to aging i mean we know what happens for example um you know when a brain atrophies um as we age and especially people who are impacted by neurodegeneration but we when we talk about the brain blood barrier and aging what do we know so uh i make it easy for you and for other listeners the blood-brain barrier the way that we say it so it's easier and shorter bbb bbb okay the triple b so um [Music] so what we know is that uh for normal brain function the blood-brain barrier works well and it's a filtration system and the other thing that was known in the field for many years uh was the observation that in some neurological actually most of the neurological disorders you will see some um dysfunction of the blood-brain barrier but as you know you talked about atrophy you see dysfunction of brain components and one of the brain components that you see this function is is this blood-brain barrier is this bbb um but you know that could be something that just epi phenomena this hap you know this and this happens it doesn't necessarily uh cause one another um we had early on some um years ago started with asking a question about traumatic brain injuries actually so traumatic brain injuries uh there is an actual injury to the blood-brain barrier and we had some idea that this might actually be part of the disease development meaning in patients where you will see a specific dysfunction sustained prolonged dysfunction of the blood-brain barrier maybe that actually causes the downstream neurological effects in those patients so we studied that we understood a lot of them it turned out to be true that's that is indeed the case you can actually um take out the whole injury part and only manipulate the blood and bear we we would open it locally and just wait and see what happens right and over weeks and months this uh brain tissue will develop pathologies and in in when we started understanding a lot of the process and the steps in between there's a blood molecule a protein in the blood that actually gets access to the brain and then binds the receptor and then activates and then there's inflammatory and everything that follows that um and then we started thinking it it you know it looks very similar to something that might happen in a lot of other conditions one of them possibly is aging and we don't understand a lot about the natural aging of the brain so before we talk about atrophy neurodegeneration just a regular process of aging we thought maybe that can explain it um and so that's that's the newest uh set of papers that we wanted to talk about where we actually showed that it plays a role so there is this function of this barrier um when we we showed it in mice and we showed it in humans and when you follow a population of mice or a population of humans you can see that um most will have an intact blood-brain barrier in their 20s and in their 30s we looked at human some do not but most will and then as you go towards middle age you see some people start having some dysfunction of the blood and barrier and when you get to about 70 years old there is somewhere around 75 percent of the population showed some dysfunction of blood-brain barrier so how do you see this um is this through a pet scan like how can you as a scientist look at our brain blood barriers and see that there may be leakage or deterioration multiple ways so when we do it with patients there's a dynamic contrast enhanced mri protocol meaning we have a contrast agent the contrast system is injected into the subject in um iv and if the blubbering barrier is intact it cannot get into the brain so we only see it in the circulation but the brain when we scan it is still very clean and then if there is um dysfunction of the budget barrier it will leak into the brain and you start seeing signal in the brain and and we can create maps and this is a technology that uh was developed by my collaborator elon friedman in dalhousie university and he um he scanned at this point hundreds of patients and created an algorithm that now makes a permeability map and quantifies the amount of leakage that one sees and where it is in the brain so that's one way that we can see it we could do the same mri on on our animals and the other way is we take brain sections but this is postmortem after the animal or the person is no longer alive you can take their brain and stain or quantify in other means blood proteins in it and so we've done that as well we've done postmortem studies on humans and on mice right okay we're getting we're getting um uh several questions and um someone is asking with smoking and or poor sleep damage the uh bbb no that's a good question right so what exactly causes this damage in the blood-brain barrier and we don't know this is something that we're studying now in the lab and there's a lot of other labs that are becoming more and more interested in that so you know this is sort of a neglected area of neuroscience is thinking about the vascular function so we know less about that what we actually the way that we got into this field to begin with was when i was a graduate student and alone was a physician in the israeli army many years ago in in the 90s in israel we started with a study that looked at the effects of stress so you know my other as you mentioned my other half of the my other half of the brain is concerned with stress and we had we looked at the fact of stress and it turned out that acute traumatic stress actually causes the leakage uh in the blood barrier as well so you know when when your listener is asking about sleep poor sleep is something that causes uh stress or there's mechanisms of stress that are activated with poor sleep so yeah that might be uh we also know that there are some diurnal changes throughout the day and night there are changes in the um dynamic uh function of the button barrier so we think that um there are important parts there and there are other mechanisms that are beginning to be revealed that sleep for example is very important for cleaning the brain from like of protein aggregations and so on that we know are not helpful for neurodegeneration or so so sleep i think is very important there but we don't know enough yet about the mechanisms of why in some people there's this dysfunction in others we see complete resilience throughout their life okay i want to talk a little bit about your stress research and how you came about this because last time we spoke which was quite and you know a couple years ago now um you were telling me that what your research found was a little bit of stress is actually good for the brain but too much stress is actually dehabilitating is that because and at that time you were saying you know if we produce too much of certain chemicals then uh it can be very bad for our brains um also you know generated by stress so i'm wondering is it is it the brain blood barrier that it's actually harming is that the relationship there when we're too stressed out we release too much of certain um i don't know hormones chemicals what do i call them um there are hormones and there are neurotransmitters and chemicals that are released so people are very focused on the hormones that are produced in stress adrenaline and cortisol everybody knows about that um and you know so what one of the the answer to your question is i i don't exactly know that we started with looking at this acute stress um actually opening blood-brain barrier uh then uh i went on to study stress in other avenues and we went on to continue with the blood and barrier in in the realm of more traumatic brain injury and epilepsy and we didn't really make the connection and only now somehow 20 some years later we're coming to start to put them together and ask questions about how stress throughout life affects the the function of blood and bear in aging in the interaction specifically of stress aging and alzheimer's disease so we're trying to ask that also on the background of genotypes that are specifically um vulnerable right so so i i don't i don't know yet if right if you know my gut feeling yes i think the bone marrow plays a role there uh what we're working on the lab right now is a different mechanism we're looking at the plasticity of of myelin in wrong places and it's probably not one answer right it's going to be many mechanisms that contribute to different things but if you have to tell our viewers here as well tell tell our viewers what myelin is and what it does oh so myelin is um so the cells in the brain that most of us most of the the field is focused on are neurons neurons are the nerve cells they connect to one another by electrical signals and that's how the brain that that's that that's the communication language of the brain is the electrical signals that are sent between neurons now if you think about this uh think about an electrical wire for example right that you know from home there's this plastic sheath around it that insulates it and that is what um allows for a very precise uh and quick movement of ions which are the electrical charge and that's how the cells talk to one another so that is myelin myelin is this you can think about it as this plastic it's a sheath around axons which are the projections that connect cells one to another neurons okay and that actually this question is appropriate to like dissecting the you know biology of our brain um someone has asked does an endothelial dysfunction develop no endothelial cells um as i know it are the cells that are in between um the vessels isn't that right like the barriers and so the barrier is the blood and barrier the baby it's that is made from uh a few different kind of cells main ones are endothelial cells they make up the wall of the of the blood vessel and there is connections that are different uh in the in the brain capillaries than the rest of the body and they're called type junctions but as as you can imagine tight means they're tighter and less things can cross in between the cells and then also the endothelial cells have other mechanisms that suppress uh things passing via the cells themselves so trans cellular passage all sorts of mechanism and they're endothelials so endothelial cells are sort of your first round of your first line of defense and then there also from the brain side other two types of cells that are very important one is parasites and one is astrocytes and the dysfunction of the blood-brain barrier um it is much more complex than you know it's open it's closed it's actually any of those mechanisms could be uh dysfunctional it could be the endothelial cells trite junctions it could be this transcellular transport it could be the parasites it could be the astrocytes and it's probably not the same in every case and we're only starting to understand more about that and i think um we're seeing evidence of all three okay and so and us and others too that there are other papers that are starting to come out to show yeah it's it is a really interesting area to explore and i it sounds like you know it's it's good that more research is going in this direction um another question is are concussions typically associated with transient disruption of the blood rain barrier so depends on who sometimes is it's transient we we've looked uh we've worked with uh football players that's that's the most um uh obvious uh ways to show that and some of them it's it's you know some of them do not have uh blood and bare dysfunction some of them have a blood and bare dysfunction and the next time that you scan them they're fine and some of them we get to see a year later and there's still dysfunction there so this dynamic effect the dysfunction of the bloody rare and then it heals in some people but it doesn't heal in others we don't understand yet we know we document and we see that that's the case but we don't understand why in some people it's like this and some um it's different it's very clear that repeated concussions or repeated um mild traumatic brain injuries are something that exacerbates that so if we look at animals and we we they would get this very very very mild hit actually you know you you can't even see and they wake up from the anesthesia and they go away they're fine the second time they're okay third fourth time we start seeing effects of that both neurologically like symptoms but also on the blood-brain barrier oh interestingly when we scan their brains we could see that there's a deterioration with each uh additional hit the additional hit of anesthesia of know of this of concussion let's say the concussion oh okay okay compression yeah and the tissue is actually protective is it yeah in the in the animals at least it is interesting yeah so so i should say that daniella just um recently published an article in scientific american and one of the things that i was encouraged by is within this article you say um that you that um a leaky brain blood barrier has to be considered um and that actually what gives you optimism is the results of your work strongly hints that the aging brain retains a capacity for reshaping and restoring itself that to me caught my attention because is it is it kind of like the the liver like are we is our body uh capable of repair um in certain aspects of the brain because we often think of um brains we think of neurodegeneration a a non-reversible condition so that made me really perk up and think well what does that exactly mean right so you know that that was i think to me one of the most the highlight of optimism in my career i think was that because this wasn't control right so the way that i understand the process the way that we were starting to unv unveil what the process is is there's this cascade of events right with the protein and it gets in and it activates and then there's um a lot of inflammation very very massive inflammation inflammatory response of the brain and then it changes um wiring and it increases excitation and it decreases inhibition and all of those things that lead to neuropathology so we understand that this is a process that takes long i thought this is lovely we found a an initial event and we knew that the event is very important because we could take a very young mouse and just inject this protein and then start following it and in few weeks this mouth brain look like and functions like an old brain so you know you don't even need other components of the aging process this was enough to recapitulate that this is okay so now let's do the opposite let's see if we can block it right so what do we do let's take young middle-aged animals we block it and now we let them age and we prevented it from happening and that was the case and it's okay so now we take another control for that and the control would be we will take them after the damage is already done we're going to take aged animals and block this process and see what happens and you know if i had to put my money then and bet on the result i would say the result is you can't right the the damage has already been done as you said newer degeneration that there's plasticity of the of those sites of those newer circuits it's it's it happened we're not going to be able to reverse that and that negative control group ended up being a really interesting experimental control group and then we repeated that in all sorts of different ways we blocked it pharmacologically and we blocked it genetically and we tried a lot of different things and all the results were that in fact in an age brain so remember this is not this is not neurodegenerative model this is not massive neurodegeneration happen just regular aging but in an aged animal where you already see signs of of neural dysfunction when you block this you restore an environment for the brain where the blood-brain barrier is now intact we can fix the blood-brain barrier the inflammation goes down and within days we start seeing uh neural activity normalizes it's like a fog it's like there's this inflammatory fog that just sits on the brain and when we remove that the capacity the plastic capacity in the normal neural function it's there so yeah so the brain can sort of we help restore by fixing the blood-brain barrier and from there on the brain just acts in in every way that we measured lots of different ways to measure it was acting like a young brain animals were learning mazes like young brains they inflammatory response was down the we're recording their neural activity um with something like an eeg so it's it's the electrodes are on are directly on the cortex and not on the skull but we're recording this activity over days they normalized it was very beautiful and very optimistic that's amazing um that's yeah that's that's amazing where do you go next with that research though so a lot of different directions um one of them is is trying to see if this could be something that is developed as a drug because the capacities is incredible um and so we're trying that uh in alzheimer uh models as well because we know that blood member dysfunction is actually a very early event in alzheimer and so that is an avenue that's very interesting to us uh we're trying to understand the mechanism you know your your initial question why why does it happen or why doesn't happen in some people and not others uh we're understanding that there's an importance to where it is actually um you can see it in some psychiatric disorders as well but that's in different brain areas so the importance of where the dysfunction is localized um we're seeing some too early to talk about that but we're seeing differences with sex and so that's um it might be a different mechanism between men and women um and we want to see the effect of your life history right things that happened before um [Music] stress would be one of them but exercise nutrition all sorts of different things that can actually um affect your blood grain barrier and i i think it'll be really interesting to understand those okay i want to talk a little bit i see that we're getting some comments on people um saying that you know they have many uh family members with alzheimer's and i and that reminded me that i want to talk a little bit about the genetic component because um previous research has shown that even healthy people with apoe4 so if they have i don't know if it's homozygous or heterozygous one or two copies of that gene have greater damage to the blood-brain barrier than those without e4 now can you tell us a little bit about that that's fascinating to me what do we know and what's the relationship with genetics to make you more predisposed to having damage on your um on on your bbb yeah i think the extent of what we know right now is right about what you said is there's a very strong correlation um you know when we look at the genetics of of alzheimer it seems that the the biggest predisposition that you find in in general population sporadic cases not not you know there are some known mutations in in the amyloid pathway but outside of that it's the it's indeed the apoe um variant and in a new paper that showed that apoe um carriers ap4 carriers have or might have a tendency to have disruption of their blood-brand barrier um and it's now you know this is we know why do we know why no not not yet any hypotheses out there as to what that relationship may be um i think not not substantial enough yet not yet that we know but it's new data that's coming out and um there's going to be a lot more understanding of it and i think it comes at the same time that you know a lot more attention is now given to the blood grain barrier and so i'm sure in the next few years we'll find a lot more about the why so we we often speak of the brain blood barrier as in the context of microbes getting in right things that aren't that shouldn't be there so what is there your research um is there is there any research about that like what like could i mean we we've talked about viruses in relation to alzheimer's right so is is it possible that the if you have a weaker um blood-brain barrier then perhaps you could be more susceptible to microbes coming in or how does that all work am i explaining it in in too simple you're explaining it beautifully yeah so most um most pathogens don't you know wouldn't necessarily cross the blood-brain barrier some do but mostly they don't and so they don't get a access to the brain and that is when we try to explain why the bloodborne barrier this is one of the you know one of the explanations we want to protect the brain you know so the environment is such that it is protected from pathogens now when we say there's a dysfunction of the blood and bear does that mean that anything can go in no it doesn't mean that right so it's selective so you really want to think about it as a filtration system that changes selectivity it becomes a little less selective but it doesn't mean that everything from the blood now spills into the brain but there are definitely um thoughts about yes sometimes it could be in a way that viruses can get access to the brain and you get now um yeah you can see viruses you can see cells in the brain cells from the immune system or maybe you can think about cancer cells that might get access to the brain this way um we have someone actually specifically asking about fungal infections can they cause damage can they break um the the bbb causing damage and the onset of alzheimer's yeah you know that's that's a really interesting way to put it because it does go both ways right and so you can imagine that if the blood barrier is dysfunctional because of some reason and and fungal infection for example would have access to the brain tissue that would be very damaging but also inflammatory big inflammatory response in the periphery can cause a leakage of the blood room barrier and so that could be a cause for opening of the blood and barrier that then lets the access in do you have daniella i mean i've been you know keeping abreast of latest technologies and research one of them being focused ultrasound which um is beginning to uh be studied in the context of getting medications to specific parts of the brain but actually i think technically what that technology does is it really opens up the blood-brain barrier so do you have any thoughts on that is that is that a dangerous thing to do is that that could that be a i'm just wondering if someone a scientist who studies uh the blood-brain barrier what your thoughts are yeah so you know sometimes it's critical to get drugs into the brain brain cancer would be the one of the very obvious um examples you want chemotherapy drugs to get in and they don't cross and the biggest problem is how to get the drugs in and in fact you can't find um in the pharmaceutical industry some companies that are thinking about how to open the blood and barrier because they need to get things in we don't really have anybody i think or that i know of that is working on how do we close it uh to to to restore the healthy environment of the brain um so sometimes it's critical you have to open the blood and bear to get some drugs in right um i think the one of the critical issues there is going to be the timing and so if it's a transient opening and it heals right back then that probably doesn't do anything we you know we can infuse this protein from the blood directly into the brain but if it's for a very short time it doesn't do anything it needs to be more sustained so a chronic opening of the butter and barrier i think horrible idea but um but if it's something short to get something in that may not have the same effects and i think you know it depends what you do it for but usually you wouldn't do it just for fun it's done only when really necessary so how do how should we look at research on the blood brain barrier is it um is it a step cl like are where are we going with this is it you know the more we learn about this the more we can control maybe what enters the brain and what doesn't or is it um you know making um drugs different drug therapies to strengthen our uh blood brain barrier where is the research heading in all of this and how do we as people who are not in the scientific community view this research in the context of unlocking um some of the mysteries behind alzheimer's disease yeah i think the the the key here is that it become it became clear to um to many many different scientists in a lot of different places that the mechanism itself is um it's much more important and plays a role in mechanism of disease it is not a byproduct of it's not something that exists there and all we need to think about it is mechanically how do we open it up so drugs get in and that's that's where the field have been for a very long time and now it's clear that this is part of signaling mechanism in the brain and there's actually pathways that are um activated by the this disorder and in that there are many many different layers and levels of the of the selectivity there and once we get an understanding of that then i think we're going to be a lot more equipped to try to design very selective drugs and be you know use technology for that so you might think about clever ways to get things into the brain if we understand very well how the process works we don't necessarily just have to blust with ultrasound and open locally bloodline barriers so that things can get everything can get in but maybe we could actually get in only what we really want to get in and direct and target those um those particles in you know one of the most important um advances and the the newest um nobel laureate done for diana is gene editing right and so you can imagine neurological disorders if you want to do some gene editing in the brain also you're going to have to have access into the brain cells to those to the machinery that's involved in that um so there's there will be a lot more i think uh research into technologies that will allow and when i say technologies i also mean pharmacology um as well as the different um technologies that that will let us control the uh the selectivity of the filtration what gets in what's get out the timing of that and um and where right so you can imagine at the end something you know can you be so precise as to say i want you know an opening that will last for 30 minutes in the hippocampus while i only let this one particle in then i need it to be closed up again if you could be that precise yeah it's fascinating what's the next phase of your research um you know now i i mean i would encourage everyone to read the scientific american paper that you wrote but what's coming next what do we have to look forward to so for us what's coming next is understanding the inter-individual variation what what happens in different people i think understanding resilience is really important so both in stress and in the aging research that we do we're trying to understand not only what goes wrong in some people but understand how some people are protected and with stress for example we find that it's an active process this is not that something happens in some brains and therefore and nothing happens in the brain that undergo stress and became and didn't show a behavioral effect for example but there's actually a very active process of the brain to compensate so there's massive gene expression that happens in those resilient brains and so we want to understand that so in this whole process and and try to tie it now to story in which we start to understand brain function throughout life so i have to tell you every time since i talked to you about your research on stress every time i'm getting stressed out about something i stop and i i take a deep breath and i think about what you told me a little bit of stress is okay too much no you know so you did have a big influence on my life oh yay that's great so um also um people want to know where they can read about more about your research is there a place um i think uc berkeley has a page we can link to is that right um danielle right right yeah and i think the scientific american explains it in in um in in more late terms and then the science translational medicine uh is an open access uh two papers that anybody can can get to um and if yeah if you go into berkeley news and just type my name you will see all the news that okay we'll we'll post it to um in in the chat of this talk but thank you so much danielle i love talking to you every time i talk to you i feel like i learned so much i learned a ton today on the the blood brain barrier and we wish you all the luck with your research don't forget to come back and tell us every time you have a new discovery we like to keep up with the research and a lot of our members of our in our community um impacted by alzheimer's or who have the alzheimer's and the apoe4 gene um i'm sure would love to hear more in particular about this research so thank you so much for joining thank you guys for having me love the opportunity so if you've missed any of this interview um don't forget that you can um view it on beingpatient.com don't forget to sign up for our newsletters that's when we tell you what the next talk is coming up i'm really excited to keep abreast of daniella's research so thanks so much for joining us again and we look forward to having you on again thanks bye

2021-07-22 02:35

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