Novel Technologies for Alzheimer’s and Dementia Treatments

hello everyone welcome to tonight's event my name is tracy johnson and i'm the dean of the division of life sciences here at ucla and i just want to mention a few housekeeping items before we begin this event is being recorded so both the chat and the q a functions have been disabled and due to our large number of attendees which is very exciting unfortunately we won't be able to take your questions in real time so thank you to all of you who submitted your questions in advance and we're going to try to address as many of those as possible so i'd now like to welcome you to our special virtual event novel technologies for alzheimer's and dementia treatments featuring some of our remarkable faculty in the molecular biology institute here at ucla but before i introduce you to today's moderator professor and interim director of the molecular biology institute dr hillary culler please allow me to the opportunity to tell you a little bit more about the molecular biology institute's amazing faculty and students the mbi molecular biology institute is home to world-class faculty and students who are studying a wide spectrum of research areas that include but are it's not limited to biochemistry biophysics structural biology cell and developmental biology gene regulation immunity microbes and molecular pathogenesis so the mbi was established in 1967 by the visionary nobel prize winning scientist paul boyer and it was meant to serve as a hub for interactions between scientific groups on campus that was really focused on deciphering molecular structures and identifying regulatory crosstalk between living organisms since its inception just over 50 years ago the mbi has been a catalyst for intellectual exchange across disciplines and has been able to transcend departmental barriers so in fact when i first came to ucla some eight years ago the mbi was a major draw and it was clear to me that the cross-disciplinary interactions between within the mbi community would really take our research to in new and unexpected directions and this has absolutely been the case so the mbi is really a stellar institute and uh now i'm pleased to introduce you to its stellar interim director dr hilary caller so dr recaller dr kohler received her undergraduate degree in biochemistry and molecular biology at harvard university and she received her phd in toxicology at mit where she studied the role of environmental chemicals as mutagenic agents in human tissue the mission of the color lab here at ucla is to apply modern approaches drawn from molecular and cellular biology genomics computer science systems biology chemistry and medicine all to gain an insight into the molecular basis of a process called senescence which is important and has important implications for health and disease including cancer dr kohler's research on the transition between quiescence and proliferation could have major implications for healing chronic wounds and developing methods to regenerate damaged and diseased tissues and organs many tissue-specific stem cells are in fact programmed to remain in a state of quiescence in order to avoid unnecessary cell division so when injury is detected these cells can enter into an active phase to produce cells that are needed to repair damage if these cells are not able to re-enter the active state full repair is not possible which can contribute to chronic wounds and other disorders this is just one example of many of the work in the color lab that has far-reaching and important implications hillary has a history of just doing beautiful beautiful research and we're really thrilled to have her here tonight as our moderator for this evening's event so please join me in welcoming dr hilary kohler good evening dean johnson thank you so much for that kind introduction and thank you so much for your support from the molecular biology institute thanks to all of you for joining us this evening i have the distinct honor of leading the ucla molecular biology institute and i'm really delighted to welcome you to the webinar this evening the mbi facilitates research in modern biology by bringing together researchers with backgrounds in different aspects of molecular biology and helping them to work together to bring these different approaches to critical biological and medical problems today you'll be hearing one really exciting example which is the work of three different mbi faculty members who are all working on understanding alzheimer's disease alzheimer's disease is a type of dementia that affects memory thinking and behavior it's the most common cause of dementia which is a general term for loss of memory alzheimer's disease occurs when memory loss is serious enough to interfere with daily life and sadly alzheimer's disease is progressive in that it worsens with time and we don't have cures at the present so an estimated 66.2 million americans age 65 and older are living with alzheimer's today that is one in nine people who are 65 or older has alzheimer's dementia it's more common in women black americans and hispanic americans and sadly by 2050 a projected 12.7 million people age 65 and older are expected to have alzheimer's so alzheimer's disease is characterized by an advancement through the through the brain so at the beginning of alzheimer's disease there's often a loss of neurons and this can usually affect the parts of the brain that are involved with learning as it advances the symptoms can become more severe and it can result in loss of memory disorientation and confusion there are two different types of molecular structures that are believed to underlie alzheimer's disease so one are plaques and these plaques represent deposits of a protein fragment called beta amyloid and it can build up in the spaces between the neurons the other are these neurofilaments or tangles and they are twisted molecules that represent the protein tau that can build up within the nerve cells and it's thought that the buildup of these aggregates can impede the communication between nerve cells and lead to their death during the progression of alzheimer's disease both the plaques and the tau fragments neurofilaments will accumulate and associated with this will be increased inflammation a loss of neurons and a loss of synapses during the accumulation of these phosphorylated neurofilaments what happens is that these tau filaments can be normally associated with these stabilized microtubules which are kind of like the roadways of the cell once they become highly phosphorylated they can leave the microtubules and clump together to form these neurofilament tangles and it's been seen and this is a recent paper in science translational medicine from 2020 that the accumulation of these tau neurons one of the reasons that the disease seems to be progressive is that these tile fibrils can build up within a cell and then they can be passed to another cell so it's thought that this might represent one of the ways in which uh alzheimer's disease progresses um over the course of time is the spreading of these uh tau tau aggregates so today we're going to be hearing from three fantastic mbi faculty who are going to be telling you about their research um we're first going to hear about from tamir ghonin he's a professor who is developing new technologies for protein structure we'll then hear from professor jose rodriguez who is uncovering the structure of proteins that contribute to alzheimer's disease and finally we'll hear from dr david eisenberg who is going to be telling you about how we use the pro information about these protein structures to develop new alzheimer's treatments and with that i'd like to introduce our first speaker who is professor tamir ghonin professor gonin is professor in biological chemistry and physiology he's an hhmi investigator and he's the founding director of the micro ed imaging center dr gohnan's lab focuses on the structures of membrane proteins important in homeostasis and signaling dr gohnan and his lab are pioneers in developing an exciting new tool in structural biology called microed that has revolutionized our ability to study membrane proteins at atomic resolution from vanishingly small crystals dr gohnan earned a bs in organic inorganic chemistry and biological sciences and a doctorate of philosophy from the university of auckland in new zealand he continued his postdoctoral studies at the harvard medical school please join me in welcoming dr tamir gonan thank you for the kind introduction um today i'm going to be telling you about uh a structural biology method that we've been developing in my lab for the past 10 years or so and explain to you how we're using it to unravel mechanisms that lead to dementia and using that structural information to help design new pharmaceuticals and new treatments for dementia now we're all structural biologists um the three speakers today we're structural biologists and structural biology is a branch of biochemistry that is concerned with how biological micro molecules are built and that means when you have a protein we're trying to figure out how they're built and then based on the structure to try to figure out what they do what goes wrong in disease and then use that structural information to try to figure out uh what kind of drugs we could design to help those proteins along with performing their jobs and structural biology has been incredibly important since the early days when watson and crete determined the structure of dna which helped explain to us how genetic information is inherited now how does structural biology works it starts with a crystal uh now a crystal you can think of a crystal as a three-dimensional object with repeat structural motifs inside so here are two crystals uh you probably recognize these one of them is very useful one of them not so much and i'll leave it up to you to decide which is which both of these crystals are made out of exactly the same atom this is just carbon and you see that in this case the arrangement of atoms is very different than the arrangement of atoms here so that illustrates why it is important to understand the molecular structure of materials uh because that explains to us something about the properties that we that we have to deal with so you have a crystal and you shoot at it a coherent beam in our case it's electrons in an electron microscope and that beam will get scattered and it gets scattered in predictable ways we record this scattering uh on a fast camera and based on that uh scattering which we also call a diffraction pattern we can calculate back and say what would would have been the structure of this molecule here in the crystal that would give us a diffraction pattern that looks um like what we recorded now uh uh in my lab as i mentioned we've developed a method that's called uh microad which stands for microcrystal electron diffraction and um it's a method that uses electrons as the coherent beam and because electrons are so efficient with interacting with matter we can get away with crystals that are invisible to the eyes so the crystals are so small you don't even see them uh and um they're about a billionth the size of what you need for other methods now these are the kinds of electron microscopes that we need they're incredibly impressive to look at they're even more fun to use uh this particular one is is a microscope that we have at ucla we have a similar one at ucla it's not this exact one but um it's 14 feet tall it's incredibly uh complex and it has the ability to let us see atoms uh the information of course is quite rich and it needs uh very big computer clusters to do the image processing and so we rely on heavy computations for for our work as well now how does microad work we start with a small disc it's about three millimeters in diameter and inside we have those crystals that i told you about and you see that they're moving because it's at room temperature but now we're going to freeze them and we freeze them because that stops the movement it helps us focus on them and also protects them from radiation damage we put the sample into the electron microscope uh and so that is all done under cryogenic conditions so very cold temperatures we focus the electron beam on a crystal and we start rotating the stage so the stage is continuously rotating while we're collecting the data and the data is recorded on a fast camera as a movie and of course uh at the end of that movie what you end up with are many many different frames and each frame has one of those diffraction patterns that i told you about and because we were rotating we get all the different views of the molecule this is one such example and you see all these reflections all these spots we give them a position in x y and z and then we extract from them the intensity how strong that peak was and that of course tells us something about the underlying structure because all this data came from a single crystal we can fit everything together like a puzzle in three dimensions and figure out what the entire three-dimensional pattern looks like and based on this we can then use the computational resources to try to figure out what the structure would have been to give rise to such a pattern and in this case i'm showing you a structure of an enzyme that we determined in the lab to atomic resolution by this method now what i'm going to tell you today about is how we use my greedy to try to understand what happens in dementia now there are some terms here that we need to become familiar with one of them is that your brain is filled with receptors your brain is wired it's wired to receive senses from the world it senses your environment and what does the sensing are these receptors so when you eat something that is uh hot it is a receptor that tells your uh your your your body that um the the the food is very spicy if you touch something that is uh physically hot um again it's those receptors that tell your hand to move back uh move away and uh and be safe now these wires uh are all interconnected and when they start um to fail in sending and receiving messages that's when you end up with a condition that we know as dementia and it's important to understand that dementia is not a single disease it's actually it actually describes uh a combination of symptoms that together start affecting the quality of life that folks experience and so this is just an example of the kinds of losses in sensing that happens in dementia now your brain is wired through these long cells that are called neurons there are thousands of them in your brain and they're all connected with one another and signals are sent and received so in this simulation here you can simulate this uh uh receptor in this area and you see that the signal gets propagated and is sent uh throughout your brain to the correct place so that you can then induce the correct response now you may have seen pictures like these where these connections are these connections between neurons which are called synaptos are illustrated like this cartoon over here if you were actually looking at this in an electron microscope this is what you might see so here is one neuron here is the opposing neuron and right here is a synapse they're making a synapse and this is how they this is where they communicate through and if you were to blow this up and look at it closely in three dimensions you would see that this is a membrane and it's filled with these receptors that i was telling you about so in my lab we have a way of um extracting these receptors we induce them to form these crystals so now you see these crystals they're not diamonds they're actually from these receptors and you can use these receptor crystals in microad to obtain your diffraction data and based on that diffraction data you can then determine a structure in this case i'm just showing you an example of one of those receptors and you see that on this side here of the receptor there are these cholesterols bound and there is a drug that we found right here in the um antagonist pocket so this is an inhibitor and once the drug binds here that sends a message to the inside of the cell where this part of the protein can then send the signals and we're now using microad to solve and determine many different of these uh structures of these receptors with different drugs and then the underlying goal is to identify and design new treatments for the marine shop based on a structural approach and with that i'd like to thank you for your attention thank you so much dr gonan it's really fascinating to hear about your amazing technological advantages advances for determining protein structure next i have the pleasure of introducing dr jose rodriguez dr regas rodriguez is an assistant professor in the department of chemistry and biochemistry his lab studies the complex architecture of biological systems from single biomolecules to cellular assemblies at high resolution his work combines computational biochemical and biophysical experiments dr rodriguez received a bs in biophysics and his phd in molecular biology at ucla please join me in welcoming dr jose rodriguez thank you it's a an incredible pleasure to be here with uh our remarkable panelists this evening uh wonderful colleagues that are all part of the molecular biology institute i'm going to pick off uh pick up where uh dr gonan left off talking about proteins that are incredibly important for uh the functions that we uh perform in our daily lives and uh essential for all parts of life um when proteins behave normally they allow us to experience the world around us uh to be human but when they don't perform normally we can encounter fundamental inabilities to perform essential tasks and i'm going to talk about what happens when proteins don't perform normally specifically a particular situation where proteins self-associate and form aggregates that are difficult for the body to deal with and why that is associated with a condition like alzheimer's disease now we've heard about how alzheimer's is a disease of the brain and uh you can see indeed that in an alzheimer's brain there is a significant amount of damage uh compared to a normal brain in fact if you zoom in and take images of the types of neural networks in the brain that professor gonan was presenting in his presentation you can see that in the alzheimer's brain you see an incredible number of deposits of proteins that are difficult for the body to clear a large deposit is shown here and it's difficult to make out the structure of the deposit itself but if you were to disentangle the proteins to some extent in that deposit what you find is that it's filled with these filamentous structures these structures are not one protein but many thousands of proteins that have all come together to form this one structure they are found throughout the brain but they appear progressively as the disease worsens you see more of them spreading throughout the brain ultimately affecting essentially all regions now it's difficult to understand how it is that these molecules come together and associate uh but it's helpful to think about it in terms of a simple analogy the way we understand things as scientists is through observation and through a relationship of uh our understanding of the molecules to uh our understanding of uh daily objects in the real world and so when i think about molecules coming together i think about a simple situation like a lock and a key a lock and a key might come together to interact with each other unlock the lock and uh they even have a specific mechanism for doing so but what happens if uh by some sort of aberration you create or encounter a version of a lock and a key that are one where the key is able to unlock itself then you can imagine these can come together almost at infinitum and so you can encounter a propagative event where the same molecule sticks to itself and creates many many many uh layers of this particular assembly now in the very same way two particular proteins happen to do the same thing in alzheimer's disease these two proteins are amyloid beta and tau they're not in fact locks and keys they're complicated molecular structures that are encoded by our own genome they're proteins like the ones that professor gonan described and they assemble with other copies of themselves to form these very long filaments in fact if we were to zoom in to one of these filaments we can see you can vision that there are many many copies identical copies of the same molecule stacked up through these horizontal layers that you see in this uh now atomic rendition of the structure found in these filaments each one of these layers is now uh a serpentine structure formed by the protein each one of these arrows in this magnified cartoon of a small region of this structure show you how complicated the serpentine behavior of the fold can be and each one of the layers now represents a different protein adding to this assemble now when we think about trying to tackle the problem of dealing with these assemblies we have to attack it from multiple multiple perspectives my group and others in the mbi are thinking about these types of self-assembling molecules uh from the point of view of uh how it is that they uh come together what it is that they look like at an atomic scale uh and so we employ multiple tools to to assess that we employ biochemical characterization by physical characterization we try in some cases to reconstitute the assemblies from scratch to see whether or not we truly do understand how it is that they come together we also try to assess whether or not in a petri dish for example they might impact harm or induce some kind of pathology we also can use animal models to try and test out whether or not the pathologies are also propagated in real life settings and ultimately we try to partner with those who can help us determine how to inhibit the types of pathologies that lead to disease we rely heavily on the types of tools that professor gonan described including electron microscopes one of which you can see on the left hand side of this slide next to one of the staff scientists that we have that ensures that the microscopes operate properly the samples that go into these machines are incredibly miniscule in fact a tiny drop of liquid can contain thousands of these filaments that can be found in the brains of alzheimer's patients you can image them directly the filaments shown here are examples of these types of molecules and if again we were to zoom in we would see their atomic structure but it's not so straightforward to actually witness that atomic structure so in fact to achieve this we have to assemble teams like the members on this panel to try to and actually uh reconstitute and sometimes visualize the exact arrangement of atoms present in these complex assemblies so to do so for example we might take an assembly like this that represents this complex filament and we might use the tools the electron microscopes at ucla to actually interrogate its structure in this case i want to highlight one such structure the structure of an amyloid forming segment that is associated with alzheimer's disease this is the product of a collaboration not only amongst the panelists that we have here tonight but also other important members of the molecular biology institute and the structure that you see a chemical representation of here in the middle is actually modeled into the blue spherical objects that we see here which are actual measurements uh visualizations of the atoms inside of the assembly this is from a side view you can see the many layers of the assembly here if you look at it from the top you can see what a single layer looks like and where every single atom in this structure is and that's the remarkable power of partnering together with the panelists to visualize these molecules again this is a true team effort of many many members of the molecular biology institute some of whom are highlighted here below and it's a real pleasure to be part of this team thank you so much dr rodriguez for sharing with us your interesting research on the atomic structures of proteins that contribute to the development of alzheimer's disease next i'm excited to introduce dr david eisenberg dr eisenberg is a professor of chemistry and biochemistry and biological chemistry and an investigator of the howard hughes medical institute dr eisenberg studies protein interactions with x-rays and electrons bioinformatics and biochemistry with an emphasis on disease-related proteins professor eisenberg's work has helped us to discover protein states that contribute to the development of alzheimer's he and his lab members are using this information to guide discovery of molecules that can diagnose and treat alzheimer's and parkinson's disease dr eisenberg received his undergraduate degree in biochemical sciences from harvard college and his doctor of the philosophy and theoretical chemistry on the rhodes scholarship at oxford university please join me in welcoming dr david eisenberg thank you hillary and tracy for making ucla such a great place to make discoveries and i really thank my collaborators not only jose and tamir we've had wonderful time productive time working together but others at ucla we are so fortunate in having basic sciences right next to our medical school makes a tremendous difference and in our lab here i list 16 of the current lab members who are staff scientists graduate students post-doctoral fellows who've worked on the projects that i'm going to briefly describe to you today i'll be summarizing about 18 years of research in eight minutes so uh first of all a little bit more about what is alzheimer's disease and how it's related to these fibers of proteins then the question that undoubtedly you're thinking about why hasn't our pharmaceutical industry been able to produce drugs and diagnostics for this disease and if they haven't been able to how can we possibly do it i'm going to show you how and the paths that we've taken are twofold first of all to discover through structure through these structures that you've been hearing about how to inhibit the formation of these fibers that cause alzheimer's disease and if the fibers are already there how can we dissolve those fibers that have already formed hillary's given some background of alzheimer's disease about how it starts in one region of the brain and then spreads to other regions and if we take the brain of the autopsy brain of a person who died from alzheimer's we see cells and we see inside the cells these so-called tangles and those if we enlarge them are fibers of the protein tau we also see these other uh aberrant structures called plaques of another protein amyloid beta both these features were seen by alzheimer's in uh alwa alzheimer's a pathologist in germany in 1906.

if we enlarge these tangles as jose showed us their fibers and you get some idea of the size of these fibers if about 10 000 are placed side by side that would be the thickness of a human hair so we have to use these tools of diffraction and electron microscopy to see them and to see where the atoms are so we can do something about it so why has pharma not come up with a drug yet well a successful drug has to reach the right target and somehow inactivate it and pharma for historical reasons has focused on not the right target they focused on the amyloid beta structures largely ignoring tau and tao is the one as hillary showed us which is correlated with the destruction of the brain pharmas also focus for drugs on antibodies well they're very good at making antibodies they're very useful drugs in cancer and other diseases so as they know how to make it so let's try it for alzheimer's but they do not efficiently get into the brain and they don't penetrate the cells in the brain where those tau fibers are and at the basis of the problems that pharma's had they've neglected to learn the atomic structures of these fibers the atomic structures are so important if you're going to do drug design you have to know where the atoms are the reason they didn't do it is they thought it was impossible to do so and i think it's our achievement at ucla working together our team has learned atomic structures of tau which is the cause of alzheimer's and alpha-synuclein which is the cause of parkinson's diseases and having seen these structures that allows us to design inhibitors of these fibers and other molecules which take them apart that disaggregate them so just to show you a detailed example which came from the combined work of tamir gona and jose rodriguez and in our laboratory here is a structure and you see individual atoms here uh so this enlargement to the my screen is about a hundred million times and we see why this these fibers are so stable they're pairs of these sheets that bond together like a zipper you can see the teeth of the zipper here and most interactions between proteins which are important in metabolism they're like fault velcro they come together and they come apart but this structure it's like glue like super glue once these fibers start to form in your brain you're very hard to get rid of so now i'm going to show you a little bit more in detail of uh how the fibers of tau how they form this is a segment of tau it's the adhesive segment and you can see the zipping together of the atoms in the tau fiber and once this fiber starts new molecules of tau add to it in elongating the fiber and causing problems and killing the cell and the tau fibers are complicated there's not only this one interface but there are three different interfaces in which these fiber grows and now we design an inhibitor here it's shown in red and that prevents other layers of tau from adding to the fiber you can see how frustrated the other the tau molecules are they can't add to the fiber anymore once we've added our inhibitor so that's how we stop fibers from growing but what about fibers that have already grown well recently we've learned how a small molecule breaks up these fibers of tau and we're now designing drugs based on this knowledge so here we see electron micrographs of fibers of tau which have come we've purified them from the brain autopsy brains of alzheimer's patients these fibers all look the same they're identical you can see these bulges on them if we add this molecule egcg which comes it's a dilute in green tea but we have a lot more of it and after three hours it breaks up a lot of the fibers if we leave it for 15 hours it breaks up almost all the fibers this is one we could see you can see it's this is fibers going on the way to destruction after 15 hours so uh because we know that egcg breaks up the fibers we determined a structure which has just recently been uh published of how egcg binds to the fibers so here i show you a magnified image of the tau fibers you can see there are two j-light shaped structures which come together at this interface i'm only showing you five layers here there are tens of thousands of layers in the alzheimer's brain fibers and i'm showing you in yellow where the egcg molecule binds and it binds like a wedge in between the place where the fibers meet and that wedge drives apart the fibers and breaks up the layers so we've learned how egcg breaks up the fibers but egcg is not a good drug because it's metabolized into other compounds as soon as you swallow egcg but this knowledge allows us to design molecules that will do the same wedge effect but can persist in blood and get into the brain and get into cells and that's what we're doing right now we've had some initial success with that tested in the test tube and now being tested in mice and we hope eventually in people so just to show you a couple of the scientists who do this work your staff scientist michael sawaya who's been working with us for 20 years and graduate students cindy chang busy at this business of determining structures i know that you may have many questions we don't have time to answer them all today but here's my email and if you send me email with other questions i'd be delighted to answer them so thanks for this opportunity to speak to you thank you so much dr eisenberg it's really inspiring to learn how the research in your laboratory is being translated into clinical studies so now we're going to continue our conversation with all three of our faculty and we're going to address as many of your questions as possible and we appreciate those of you who have provided questions in advance so the first question is how does a family get their loved one involved in a study or new treatments and for individuals who are interested in getting a loved one involved in the study my suggestion is that you contact the mary easton alzheimer center at ucla because they are enrolling patients and studies and they would be able to have a lot more information for you about the options for your loved one so the next question is is there a test to see if someone will develop alzheimer's or dementia and david maybe you can get the ball rolling on this one right so that's an excellent question and the answer is not yet but there are many efforts underway the most advanced method uses pet scanning and it's been very good for showing the amount of amyloid beta in the brain in fact it's through those images that it uh it's been discovered that amyloid beta does not on its in itself cause dementia because with pet scanning it's found that one-third of adults over 80 years of age who are perfectly normal they have normal cognition for their age group those people have brains just filled with amyloid beta yet they're fine but if you have tau aggregating your brain then you aren't demented so that's been one of the powerful results of pet scans pet scanning is also now being worked out for tau and that will be extremely helpful but their problems with pet scanning it's very radioactive so you cannot have many pet scans it's expensive i think the reimbursement now is about six thousand dollars for a pet scan and so it's not good for following progress of the disease or for testing drugs to see if they're working on a patient because you can't have that many pet scans so we need other methods there are many laboratories hoping to find a liquid biomarker that is some compound in blood or maybe cerebral spinal fluid which you can get to a spinal tap which can tell whether a patient is coming down with alzheimer's or parkinson's disease there's progress but so far there is no reliable liquid bio biomarker available to us that'll happen i'm sure in the next few years uh in our lab we're working on yet another method and it's for uh mri and mri does not use radioactivity so patients can be followed and drugs can be tested and it's about a tenth the cost of pet scanning and it's much more widely available most hospitals have mri so that's what we're doing in our lab any other comments well i want to emphasize that the development of those probes for following the progress of disease uh is absolutely uh absolutely hinges on the understanding of how the molecules that track the fibrils uh interact with the fibrils getting structures of that is absolutely a high priority and i think the work that we saw from david on the small molecules interacting with tau fibrils is just the beginning of that david can i ask a follow-up question so i was very interested in how you said that the amyloid beta doesn't track um with actual uh dementia what do you think the amyloid beta is doing there is it just a passenger or is it just a red herring the current hypothesis hillary is that a buildup of amyloid beta in the brain can trigger the start of tau aggregation but it doesn't necessarily do so so there must be other factors and then my other question was if you were able to reverse the tau aggregation would that be sufficient so would the could you get a neuron back to a healthy state and would neurons regenerate to replace the neurons well the body has amazing regenerative capacity but i can't answer your question what i think is our goal is to stop the progress of the disease so as soon as it was diagnosed by one of the new methods or by a clinical study patient uh losing his or her memory and then started to take the treatment at least i think we could stop the disease at that point whether there'd be regeneration or not i don't know and we've learned from studies of other amyloid forming proteins uh because amyloid beta and tau are not the only ones in fact [Music] synuclein was brought up the cause of parkinson's disease there are many others there's a prion protein that causes prion disease and so on many of these proteins have the same underlying mechanism of aggregation and cause of cell death and so on or it's hypothesized that they might have the same mechanism and so you can see in other cases where animal models have been employed to try to understand the aggregation of these proteins that if you halt the expression of one of these proteins after the aggregation process have has begun after disease symptoms are manifesting themselves you can get an improvement just by halting the expression of these proteins or by clearing the proteins from the brain so i was wondering the amazing wedging molecules that david was showing um could something like that be developed for alpha-synuclein could it be what hillary could could something some one of those wedging molecules could something like that be developed for alpha-synuclein also for parkinson's disease i think possibly it could and i think once one of these diseases falls through some sort of drug the others are going to follow soon after that's an excellent point learning from how to tackle one of one type of protein aggregate is almost certainly going to teach us about how to do it for others i think we need to find what those vulnerabilities are and then take that as a lead another question i had in watching the videos was how many molecules of tower are we talking about do you have a sense for that in a fiber yeah in a single fiber there might be um 10 there are tens of thousands of molecules and as you see uh there are many fibers in the brain so many millions of molecules molecules are smaller and one of the challenges there is that your body continuously makes more in fact there are proteins that your body that your body makes all the time they happen to be entangled in this way it's not what they're meant to do but your body keeps making them because it thinks that that is a normal process and so we need to combat that and um could be the origin of these diseases is there's some breakdown in the regulation of how much the body is making or a breakdown in the systems that we have uh at younger ages which take care of the fibers and get rid of them it could be that aging destroys the breakdown system as well and so one of the questions that we received is what can one do to prevent or delay the onset of alzheimer's or dementia well that's a very very good question it turns out that only about five percent of alzheimer's patients have a direct genetic cause that is it's inherited and most of those inherited alzheimer's patients will know already from because there are other family members a lot of family members also the genetically caused alzheimer's disease starts earlier probably before age 65 so that's just a small fraction the other 95 percent those cases are called sporadic meaning that it comes from some environmental or personal cause so um what what could that be uh it's it's clear that smoking is a factor in alzheimer's obesity lack of exercise disturbance of sleep all of those probably contribute of course they're correlations they're not causing effect so it's very hard to know how much each of those matters lack of exercises is also correlated with the onset of alzheimer's what has made medicine of science is the double-blinded placebo-controlled studies in which you have two groups one of which is given the drug one of which is given the placebo and neither the patient nor the doctor knows uh which group is which that's what's made medicine a science now how do you do that with something like exercise you can't have a group of people saying you can't exercise so it's tough to identify those factors but as soon as they're proposed drugs then those double-blinded studies can detect uh whether they're effective and you you may have heard there was a news report in the last couple weeks about a drug i think it's uh donataban from um biogen which is said to have a an effect on amyloid beta and it was designed to diminish amyloid beta aggregation and uh they said that it showed a small effect on patients well i read the paper new the new england journal of medicine and it's a very small effect to differentiate the placebo group from the drug group it's just a tiny difference so my guess is that it may be approved and i think that would be good it'd be something but it won't have a big effect unfortunately so if i could ask a follow-up question patients who inherit a susceptibility to dementia or specifically alzheimer's what what are the proteins that are most frequently associated there the most frequently associated proteins are either amyloid beta or its precursor protein it's cleaved off from a larger protein or the enzymes that do the cleaning excellent or you've probably heard another protein apoe they're different types of apo e if you have type 4 you're more likely to get alzheimer's disease why is that i don't think it's known why yeah okay so the the next question that we received in advance was what type of technological advances do you see in the next decade for this type of research and tamir maybe you'd like to start the violence on this one yeah so over the last uh 10 years or so the field of electron microscopy is really taking off and so now we can investigate things that are much smaller and a lot easier to obtain so you can in the case of the samples that david and jose for example are taking you can extract those directly from brains and look at the morphologies directly from the cells and so that is i think groundbreaking technology that's going to become very important in the next decade or so because simply because we weren't able to do these type of things uh before and so as new technologies are developed better cameras more powerful microscopes uh new lasers uh new reporters that use uh fluorescence for example or you need to identify different things in in cells directly all of those are going to help with identifying these diseases i have to say the rate at which progress is being made now is remarkable um i think uh maybe david can comment more on this but from the time that the first structure of an amyloid forming segment was determined to the time that we began collaborating altogether with tamira must have been oh maybe 15 or so years and a good handful of structures were determined none from samples extracted from tissues none from you know exact uh replicas of what you might find in the brain all were constituted in the laboratory in an attempt to mimic the ones that you might find in the brain and in just the last couple of years more structures have been determined by these methods than probably in many of the previous years combined and we're fortunate to having teamwork here which makes a huge difference and we have the pathologists who help us by giving us brain samples and we have experts in the clinical aspects of these diseases in the medical school so our next question is uh also on the subject of guessing how long it will take for these treatments to become available to to patients and jose maybe want to take a step at it of course that's difficult to precisely pin down but what's important is that we don't know when the next breakthrough is going to come and so i think we've learned that in many other aspects of science we're in the middle of a pandemic that we never anticipated would happen and yet basic science has been able to pull us through every time because our investments in basic science pay off with remarkable dividends and so i think what we need to keep doing is investigating finding possible avenues for treatment and sooner rather than later i think we will get there maybe i could add that um uh you know everybody is doing the best they can with the equipment that they have and with the technologies that they have and then once in a while there is a disruptive technology that arrives um and that makes things a lot easier and a lot faster and then the floodgates open and then all these structures come in and that's what um jose was alluding to uh um just a few minutes ago and so it's important to invest in those technologies it's important to have that kind of support so that these disruptive technologies can be developed and that would then help with the design of all these new drugs because when we have those disruptive technologies suddenly we see things in a new way and suddenly we see things that we might have missed before and that then clicks together and makes it uh possible to design new and innovative drugs great and then the the last question for the evening has to do with collaborative research so maybe you can talk a little bit about what it's like to be part of a team working on a problem well maybe i could start off with a story uh in december 2013 i read tamir's article in a journal he was then working at geneva research center in virginia and it was the first uh first article describing his new method microelectron diffraction so i thought this would be good for the crystals that uh jose and i were struggling with because they were so small that method could work so i emailed tamir and i said why don't we get together and work on this i didn't hear anything back so then i emailed him again i didn't hear anything back but that time it was after after the holiday and i phoned him and then he said okay can one of you come here so jose and in no time mastered the method that tamir had invented and determined that the first structure that i showed you and then we thought it's important that we have to mirror ucla so he came and joined us let me forget that i did not answer the phone for the first couple of times [Laughter] i have to say it was a remarkable uh experience to be part of the team um in many ways it was also uh you know a learning process um it's it's great to be exposed to new technologies it's amazing to be able to use them for such important research and i hope that in the years to come there are many many more such partnerships that lead to new innovations and and new discoveries well thanks so much to the three of you thank you to everyone for joining us this evening for this webinar webinar on novel technologies for alzheimer's and dementia treatments we really hope you enjoyed the presentation and the conversation this webinar has been recorded we will send a post event email with the link to the recording please feel free to share it with others thank you again for joining us tonight and have a good evening

2021-07-09 17:50

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