And now it's my pleasure to introduce another one of my colleagues, Jane Coleman, from our nursing department who will introduce Dr. Selcoe. Good afternoon. It is my privilege to introduce our third speaker today, Dr. Dennis Selcoe, who is a Vincent and Stella Colts Professor of Neurologic Diseases in the Department of Neurology at Harvard Medical School. He has been awarded numerous honors for his work in advancement of the understanding of Alzheimer's disease. Several of these honors are noted in the Nobel conference program. I thought it might be interesting for you to learn something about him that is not in the printed materials. A bit about Dennis Selcoe, the man, the making of a neuroscientist, if you will. One thing you may not know is that Dr. Selcoe hails from the Midwest, a small town named Winnicka, Illinois. He also spent some time during his youth in northern Michigan, so he's not a stranger to our climate or to our culture. By the time he was five or six years old, he had informed his parents, a businessman and a former actress, that he intended to be a physician when he grew up. Yes, you heard me correctly, five or six. Talk about a sacred vocation. He recalls incidental experiences that impacted him as a youth, for example, visiting his pediatrician and deciding that she had very cool toys. So you see his attraction began as an emotional one, which later included the scientific component. He actually credits his seventh grade teacher, Mr. Cook, for inspiring his passion for biology. He also perceives that he was fortunate to attend a large public high school that was strong in the sciences. Perhaps some of you can relate to these experiences, knowing what you wanted to study from an early age, having an unquenchable thirst for knowledge, being affected by a particular teacher, and honoring the supports around you that have assisted you in your own growth and development across the lifespan. We also know from the conference program that Dennis earned his BA from Columbia University in 1965. Did you ever wonder what a world-renowned neuroscientist majors in? Interestingly enough, he had a double major, one in pre-med and the other in American history. Incidentally, he met a woman named Polly while he was at Columbia who was destined to become his spouse of 37 years. Four short years later, he became Dr. Selko, graduating from the University of Virginia School of Medicine. He believes that one reinforcing factor after another has guided his career path. Desire, discipline, determination have certainly been evident in the evolution of his professional role. His strong interest in the mind-brain relationship led him to focus his study on psychiatry and neurology. In addition to acclimating to the rigors of the life of a medical doctor and researcher, Polly introduced Dennis to the role of fatherhood, and they have two children. The significance of the scientific advancements made by Dr. Dennis J. Selko on Alzheimer's disease has led to prestigious awards and honors, including the Dr. A. H. Heineken Prize, the first Metropolitan Life Foundation Award for Medical Research, shared with George G. Glenner, and two Merritt Awards from the National Institutes on Aging. Dr. Selko is both co-founder and co-director of the Center for Neurologic Diseases in the Department of Neurology at Brigham and Women's Hospital in Boston, Massachusetts, where he continues to see patients as well as do research. He has also served on the editorial boards of several biomedical journals, on the Neuroscience Review Committee, of the Howard Hughes Medical Institute, and on the National Advisory Council on Aging. In a recent article from the ESI publication entitled, an interview with Dr. Dennis Selko of Brigham and Women's Hospital Harvard University School of Medicine, he is quoted as saying, understanding the molecular etiology of a disease that causes so much suffering represents a wonderful way to spend one's career. It is indeed an honor for me to introduce you to our next Nobel's conference speaker, Dr. Dennis Selko. Thank you, Jane. That was wonderful. Lovely to hear. I'm very excited to be here, and I particularly thank Tim Robinson and Richard Martin and their colleagues who organize this remarkable program for the invitation to come to Minnesota, where I used to come as a kid when my dad would travel here on business and learn more about this terrific college. I am particularly glad to have the chance to attempt to deal with an important question that the first two speakers, Jay and Len, pointed to, and that is the issue of work on age-related disease. And I must say that there is no doubt, I think in anyone's mind in this large audience, that a topic like Alzheimer's has great interest. I've learned over the years that there are at least three ways that audiences get excited about the topic of Alzheimer's. The first and perhaps most appropriate is that they're just interested in a disorder that robs some of one's most human qualities. And so all of us in the audience can share that interest and that reason to listen. But the second is, frankly speaking, that some of us need to think about whether such a thing could happen to us. And indeed, I think that's particularly true of some of us who tend to sit in the first couple, three rows of big auditoriums like this, or in my lecture halls where I work. And then there are folks who are up on the bleachers, and they're very concerned and interested as well. They're perhaps a different generation. They don't have the prime seats in the front, but they listen just as carefully because they're already convinced that some of us in the front row have that disease. So for all those reasons and others, I'd like to share with you a vision of where I think the field of research on Alzheimer's disease is going. And there are three broad themes that I'd like to mention at the beginning before I get into admittedly a little bit of molecular biology, and I'm very grateful for Dr. Hayflick's tutorial. The first broad theme is that my research and the research of many, many scientists like myself is an aspect of applied research. But my point is that this is so remarkably similar to basic research that we're happily seeing a blurring of that classical distinction between basic or fundamental research on the one hand and applied research. We use the same tools. We have the same kinds of experimental designs. And I will show you today, I hope, that understanding the biology of something as interesting and complex as Alzheimer's provides direct insights into how multicellular organisms evolved on this planet. The second broad point that I'd ask you to think about as I unfold the story of Alzheimer's is that it's increasingly likely that lessons we learn from studying Alzheimer's will have something to say about disorders like Parkinson's, Huntington's, Lou Gehrig's disease, and a variety of other less well-known but equally devastating disorders of the brain and indeed even some protein folding disorders outside the brain. And Alzheimer's has arguably one of the most, if not the most common disease, implicating protein folding, can give us lessons about other diseases. And the third is really something that I hope will be relatively upbeat. And that is by studying Alzheimer's hard, we have, I think, within our vision, within our sight, the possibility of an effective set of treatments. So I think that my message is really quite upbeat. That is that Alzheimer's disease probably can be treated effectively. That's something I think we're not quite doing yet and ultimately be prevented. And I want to try to convince you of that today.  If you could look at an Alzheimer patient's brain by cutting a little window in the scalp and the skull, ouch, doesn't sound like a very nice thing to do. But in fact I think you would see the essence of what is wrong in an Alzheimer patient. So as you look at the screen, this is an artist's conception of what it might mean to have a neuron lose its ability to provide electrochemical energy from one axon to the large neuron on the top of the screen. Over the aging process and during time we know that this happens. We can freeze the frame, sadly we can't do that in our brains, and notice that this axon has lost its ability to fire electrochemical energy across to this large neuron above. This loss of axonal power, this weakening of synapses, essentially is at the center of Alzheimer's disease. And it is also true of Parkinson's and Lou Gehrig's and many other brain degenerative diseases that occur more commonly in late life. Fundamentally we like to understand why selective synapses essentially give up the ghost. And as time goes on they lose their lost completely. Now this is what I've referred to as synaptic failure and it's a centerpiece of Alzheimer's disease. Here you see examples of synaptic failure in real time in my clinic. In real time is an intended pun here. That is that in four different patients whom I asked to draw a clock and put the hands in so that it said 445, you can see that these patients with mild to moderate Alzheimer's responded in different ways. This is one way of saying 445, here's another way of writing 445. This gentleman who was a very interesting fellow in his early 70s who was a racehorse enthusiast and actually an owner of horses said, well here this is a face of a clock. And that's not what I had in mind and when I repeated the command he then drew a very correct clock putting in the hands at 445 and the lady who drew the clock in the lower right was really unable to understand the concept in any detail and could not really provide a cogent answer. This is what we see all the time and what I see on Tuesday morning is when I see patients with this dread disease. So today I want to tell you a little bit about what might be going wrong here at least from my perspective and what we're going to do about it. Alzheimer's as you know is the most common cause of dementia and I'll define my terms also as my colleagues did previously for their lectures. It affects some 3 to 4 million Americans and perhaps greater than 20 million worldwide but we don't know the precise numbers. Americans of African, Asian or European backgrounds have quite similar prevalences of Alzheimer's disease which has actually been determined by knocking on doors in places like rural Mississippi and understanding what is the community prevalence of this disorder. So it happens all over and if you're asking where there might be a hotbed of Alzheimer's disease it might be a place like South Beach in Miami or at least the way South Beach used to look before it was taken over by much younger folks. Alzheimer's happens a lot where people live a long time that is they age successfully and sadly one of their rewards for aging successfully otherwise escaping perhaps mortality from heart disease or stroke or cancer is to be subject to the possibility of Alzheimer's. It's a very expensive disease and we don't know the precise expenditures now and there's not a cure or effective treatment in the sense that we have effective treatments for infectious disease etc. I won't announce a cure today but I will at the end of my talk point to something that I think may turn out to be a potential preventative. Now let me define for you quickly the term that the general public refers to as senility. Senility is something that my colleagues and I in gerontology, geriatrics, psychiatry, neurology often think of as senile dementia and that is a progressive mental failure after age 65. It's an arbitrary age of course it really relies on the Social Security Administration which defines when retirement begins. So this is not a biomedical concept and I think many of you may know that I think even the Social Security Administration selected the age of 65 in part because Bismarck more than 100 years ago asked his ministers in Germany well when is the age that most Germans will likely expire and the answer came to Bismarck well that is 65 sir and he said well that's when we'll begin federal health insurance. Now in point of fact this is a completely man-made concept that senile dementia should be that entity after 65 and pre-senile dementia as we call it should be before 65 and it does not seem to be two diseases it's a gradual increase in prevalence not a bimodal age curve but a single rise. Let me go ahead and mention that Alzheimer's disease is the most common of more than 20 causes of the disease which I won't mention for you and it accounts for roughly a half to two-thirds of dementia cases in the U.S. It begins insidiously as so many of you know having loved ones this disorder usually with decreased episodic memory. What did I do yesterday when I got picked up at the airport? What happened after that? What did I have for breakfast? What did my wife and I do last weekend in New Hampshire? Those are the little fragments of everyday experience that tend to be lost early in the course of Alzheimer's and executive function which means carrying out a task that otherwise you feel you'd really be able to do. This progresses quite slowly usually over five to twenty or more years and it is fatal we sometimes think of Alzheimer's as not being fatal but it does provide the possibility of shortening life expectancy once you develop clinical Alzheimer's compared to a sibling or a friend who at the same age does not have Alzheimer's. Now there's some estimates about the numbers associated with the disease which perhaps explains why as Len Hayflick pointed out it does garner a lot of our attention and some of our research dollars. At age 75, and these are figures for Alzheimer's disease per se not all of dementia, it's estimated by a particularly reasonable study by Brookmeyer and colleagues that 4.3% or so of the American population have the diagnosis of Alzheimer's. And age 80 and 85 and 90 you see this number rise. It's not inevitable in my view. It's not something that happens automatically the older you get but it has a very striking age linked rise and prevalence. The incidence is some 360,000 new cases per year very inaccurate number that ranges from 200 to 600,000 and if things are unchanged and they're very unlikely to be unchanged some have figured that this number could rise threefold to 1.14 million new cases by 2050. And the prevalence by 2050 could rise as much as 3.7 fold to some 8 million or so maybe in a range of anywhere from 4 to 15 million so their stark numbers were the adversary and something we need to do much about. It's been estimated that an intervention that would delay the mean age of onset by five years would provide that therefore about a 50% reduction in risk of Alzheimer's and would reduce expected prevalence by about 1.2 million after 10 years. That is if it began in 2000 by 2010 one might expect a drop of that many cases of Alzheimer's and perhaps by 4 million after 50 years. These are drops but they're not good enough in my view and the hope is that we can be much more robust in slowing down the process. So I'm going to apologize to you for telling you a little bit biology of the disease it's a very interesting story and I don't want to scare you with the science but I think you'll find it really quite interesting. Alzheimer himself, a Bavarian psychiatrist, described the first two lesions he actually didn't first describe them but he put them together with the syndrome of a woman in her 50s who had a so-called presenial dementia and he called these lesions and referred to them as amyloid plaques and neurofibrillary tangles. Many of us studying Alzheimer's know about those lesions but there's an awful lot going on beyond that. There is an apparent inflammatory process in the brain by which I mean an activation of microglial and astrocytic cells that I'll show you in a minute. There's a selective loss of neurons, a degeneration of neurons as you'd expect and beyond the loss of neurons per se there's a pruning back of those synapses which is what I was trying to illustrate with my cartoon. The synaptic loss must provide a substrate for the multiple neurotransmitter deficits that are known.  This is the only message molecule that is currently addressed by FDA approved drugs for Alzheimer's. That is glutamate which of course can be addressed in a different way by the drug memantine is not addressed as regards this list in which glutamate actually shows deficiencies in the Alzheimer brain. So we're really only intervening with one small part of the puzzle when we treat our patients with drugs that have dramatic names like eczlon and ariset but don't necessarily do a great deal of good for the progression of Alzheimer's. Now it turns out that what Alzheimer called attention to in his paper in 1906 and by the way when he rose to speak and sat down after a few minutes questions were solicited and there wasn't a one. So I won't feel so bad if you have no questions after my lecture. I'm in good company. What Alzheimer pointed out in that lecture was that here illustrated in the brain of a patient I followed during life a 69 year old gentleman who was a stockbroker died with a family history of Alzheimer's. In the amygdala part of the brain important for aspects of emotional control there are these two round deposits or spherical deposits of protein called amyloid plaques and you see here little squiggly lines the little dark black lines just next to the amyloid plaques that represent degenerating axons and dendrites the terminals that connect neurons. Sometimes as shown over here on the right these dendrites are very thick and bulbous and dilated they shouldn't look like that and basically with this particular stain the brain should look more like the upper left hand corner. Adjacent to the two plaques you see here are tangles these as the name implies are masses of squiggly filaments of protein in the perinucleus cytoplasm that is right around the nucleus quite nicely seen in this tangle hugging the nucleus and this should not be there and you see here that in my patient at age 69 after nine years of disease there are still a set of neurons right next door that are cytologically normal we don't know if they're functionally normal but this is one of our biggest problems we don't understand why at the end of the disease neurons that are cheek by jowl with those that bear tangles or have their processes in amyloid plaques still appear morphologically normal and might in fact be normal and that perhaps explains the selectivity of Alzheimer's so you can swing a tennis racket still when you have mild to moderate Alzheimer's and you might play quite well but it's much more difficult to remember strategy and to remember the score now my wife always hates me saying that because she says that's not fair she has trouble remembering the score and I can assure you she has nary a sign of Alzheimer's but that is what happens you select some functions to be intact and other functions begin to slip here's another view here in this image and work that we did with a renowned expert in inflammation in Alzheimer's Pat McGeer Dr. McGeer and colleagues showed these dark what I call angry looking cells stained with a certain antibody that are microglial cells you see that name up here and the brown material in the back is this amyloid protein and I'm going to tell you more about on the right is another cellular element the so-called reactive astrocyte that seems to almost ring this microglial rich plaque as if it was trying to wall it off but if this is to try to clear the problem it doesn't seem to do much good and the jury's out as to whether this local inflammation around plaques is helpful or harmful or perhaps a mixture of both now I'm going to shorten a lot of interesting biochemistry that my laboratory participated in in the 1980s to define for you at the biochemical level what tangles and plaques are tangles which are inside neurons are composed of altered forms of a particular brain protein called a microtubule associated protein and the protein has been given the letter tau, the Greek letter tau so this is a normal protein and for some reason that we have to explain I'll try to provide my ideas of explanation today the tangles are a mix-up of insoluble filaments of tau the amyloid plaques which are outside cells are composed of two proteins that were named by George Glenner a very distinguished father figure in our field the amyloid beta proteins or a beta as he called them and they are in particular 40 or 42 amino acids long so just a snapshot here of the biochemistry the two lesions Alzheimer called attention to don't have an easy biochemical relationship there are two distinct proteins made by two different genes gene products and two different chromosomes now this gives me a chance to pause and reiterate a point I made at the beginning that learning about Alzheimer's might help you understand something about Parkinson's or Huntington's this table which I won't read off for you simply has three columns a column on the left of diseases a column in the middle of a particular protein implicated in those diseases and a column on the right of a locus within the brain or within a cell where that protein accumulates and if I pick up one example of Parkinson's disease down here it's increasingly apparent that a protein called alpha-synuclein a normal brain protein becomes misfolded and aggregates in the neuronal cytoplasm and that process is not so dissimilar to other proteins that accumulate in Huntington's or indeed in Alzheimer's disease as I already mentioned so this concept that there might be a common mechanism in some of these terrible diseases of late life in the brain is one that excites us it doesn't mean however that a single drug would treat all these diseases that's not out of the question but it's much more likely that lessons we learn in the Alzheimer's story will help us find drugs unique to treat Parkinson's this is a striking image it's a field of so-called amyloid deposits or amyloid plaques in the bottom there's a clear area which is the white matter of the brain and from the arrow now going up to the top of the brain section is all the gray matter of the brain the gray matter is so important we think for what we think for trying to use our minds this image is a image of the brain from a 12-year-old boy and it's remarkable to think that there could be this many myriad deposits of the amyloid beta protein or these amyloid plaques at age 12 this young man died with complications of the condition Down syndrome and we have known of this relationship for about four decades and molecular biology has shown us why it is we think that Down's patients will almost invariably develop both the plaques of Alzheimer's disease as you see here at age 12 in a patient who died for other reasons and later on the full-blown tangles and plaques and even some signs of mental failure in these patients who are already retarded to various degrees from birth on now this has been the beginning this Down syndrome connection to Alzheimer's disease of the search for genetic factors and they have put squarely in the forefront a molecule called beta amyloid precursor protein or APP let me help you through the those two of you I believe Len said who are not molecular biologists or was it six I can't remember which number was used the two of you who don't remember your details beta amyloid precursor protein is a rather elongated stick like molecule it is certainly not as straight as my schematic here but it projects out from the surface of a cell and this area called TM is the transmembrane region of this APP molecule this is the little tail and the cytoplasm inside the cell and this whole long thing can stick outside the cell so this is like an insulin receptor that allows insulin to do the many good things it does one of the strange things is that the amyloid beta protein of 40 to 42 amino acids is partly embedded within the transmembrane region and this suggested when this was first known that you know the amyloid problem in Alzheimer's must somehow be secondary it must be secondary to an injury to the membrane right here so an enzyme could come in and cut at this position and liberate just the little red box the concept was that only the little red box that is the amyloid beta protein makes up the millions of plaques in a patient's brain the rest of the protein is not directly involved in that plaque formation but we found out in 1992 that actually you don't need a pre-existing abnormality of the membrane to allow this cutting but rather that you and I do this normally throughout life and that is there are two enzyme activities two protein cutting molecules that have the nicknames beta secretase and gamma secretase that cut APP throughout your life and mine and release the red box the amyloid beta protein this suggests the possibility that if this is a normal process throughout life you don't have to have pre-existing injury to the membrane of a brain cell to release abeta and abeta could build up in some sense over the time that you age in any event and there's evidence in monkeys and dogs and in humans that indeed abeta builds up for better or worse during the aging process we now have to understand why it builds up so Jay and Len asked the question why do we age and I will ask the question why do we get Alzheimer's disease the hypothesis that I'm going to put forward is one that really rests I think originally on George Glenner's observations and one that I discussed with Glenner on many occasions and made a lot of sense to me and that is that Alzheimer's disease is a syndrome that arises from a chronic imbalance between the production and the removal or clearance of a small protein we call amyloid beta or abeta leading to its gradual cell accumulation particularly a form of abeta that has the 42 rather than 40 amino acids and is particularly prone to aggregate or clump the imbalance one imagined at the beginning and this hypothesis was formulated before we knew the genetics of Alzheimer's could be caused by distinct genetic alterations and environmental alterations are in parentheses because we know so little right now about clear-cut environmental agents that directly lead to this syndrome this is a hypothesis I'm a Baptist that is not my religious affiliation which I won't reveal to you today but it is a coined term in our field for a person who follows the beta amyloid protein hypothesis and I don't mind being labeled a Baptist I will develop some data now why I think that is the case there is a group of folks in the field who are Taoists they're not adherents to an ancient Asian religion but rather they follow the molecule Tao TAU, the subcutive of the tangles as one they feel has much importance for the pathology of Alzheimer's and of course both the Baptists and Taoists are very likely to have it right that these two molecules and many others are implicated together in the cause and mechanism of Alzheimer's disease so this is a hypothesis and it's by no means proven Schopenhauer pointed out in Germany that all truth passes through three stages first it is ridiculed second it is violently opposed and third it is accepted as being self-evident now it would be great hubris for me to think that that might happen to the amyloid hypothesis but there begins to be more and more acceptance of the notion that something that sounded not very sensible when George Glaner first proposed it could offer a fundamental explanation for why we get Alzheimer's disease and I'm going to elaborate on that theme the strongest evidence and it's important for you to understand because many of you are concerned about familial aspects of Alzheimer's and you're also concerned about therapy so this slide mentions that the strongest evidence for this hypothesis comes from the so-called genotype to phenotype relationships of genes that can cause Alzheimer's I'm not a geneticist but my colleagues in genetics have identified now four genes on four different human chromosomes that are unequivocally linked to a predilection for Alzheimer's and what people like myself have done indeed our lab and Steve Junkins lab in particular did sell biological experiments to show that in each of these four genes the arrows point up that is the beta amyloid phenotype in the brain and in simple cellular systems is an increased A-beta-42 production in the case of three of these genes and in the case of the APOE4 polymorphism not an increased production but an increased steady-state level or density of A-beta deposits so these four genes APP the first described which is that big protein that gives rise to A-beta and then APOE4 a naturally occurring variant in the population that Alan Rose and colleagues first linked to a greater likelihood of Alzheimer's and then along came Presnillin-1 that Peter Hyslop discovered and Presnillin-2 that his lab as well as Jerry Schellenberg, Rudy Tansy and others discovered these implicated genes were credibly linked to a problem with A-beta levels in the brain not just in simple cellular models as we first showed but in mouse models of Alzheimer's and in the patients themselves and three of the implicated genes increased production whereas APOE4 seems to decrease clearance in a way that I won't have time to describe to you today now let me illustrate the point with Presnillin Presnillin is so called because mutations in Presnillin cause the most aggressive form of Alzheimer's on the planet that is this particular mutation indicated by this dot here which is quite right apparently led to the development of the syndrome of Alzheimer's disease in a young lady of age 18 which is really quite remarkable she died in her 30s as a result of a Presnillin mutation that caused when we examined her brain classical Alzheimer's disease so the red dots exemplify a few of the more than 140 mutations that cause Alzheimer's and no one disputes that they can cause Alzheimer's what's unclear is how they cause Alzheimer's and if you're interested the two yellow dots exemplify two of the 6 or 8 or 10 mutations in Presnillin 2 which is a copy of Presnillin a homologue of Presnillin in molecular terms that is a bit of a weak sister it's not as important in causing Alzheimer's many less mutations and it's not as important in the biology that I'm about to explain to you so what does Presnillin do to cause Alzheimer's we speculated that mutations like this which we showed actually elevate the amount of A beta 42 protein in the patient's brain and in mouse models and in culture models that this Presnillin mutation is somehow involved in cutting APP to make that 42nd amino acid become free cut that red box out of my earlier diagram and we got evidence for that two ways one we showed that APP and Presnillin can come together and kiss each other in the cell they can form a stable complex which was a controversial observation but one that did stand the test of time and two my colleague Mike Wolf a collaborator of mine in the lab next door to me designed chemicals that look like this this is actually a series of amino acids with a green chemical a diaphragm alcohol moiety installed at this particular position and this is the sequence within APP that the enzyme called gamma secretase has to cut so the second of the two enzymes that liberates the little red box from that long APP protein that you and I have in our brains what this diagram shows is that this particular structure which is meant to mimic APP whoops I don't want to help, there we go and that this molecule can lower the amount of A beta in a dose dependent fashion and the kicker is that this particular diaphragm alcohol entity can only inhibit one kind one family of enzymes that cut proteins in biology a so-called aspartal protease so we put those two last observations together that APP and presynillin come together in a cell and that this inhibitor only would work on aspartal proteases and made an observation in 1999 and that is that presynillin has AD which is the single amino acid code for an aspartate a particular amino acid right in the middle of a transmembrane domain and likewise presynillin has a aspartate in the next transmembrane domain this is the structure of presynillin every amino acid is shown here and presynillin winds its way in and out of the plasma membrane of a neuron eight times and at time six and time seven as it passes it happens to have two and only two Ds or aspartate residues so what I'm explaining is that we jump to the conclusion that presynillin was the long sought gamma secretase a so-called aspartal protease that in contrast to every other known aspartal protease in biology cut other proteins which would lie here using two intramembrane aspartates and here's how we prove that we showed and as a title indicates that production of the abeta peptide decreases when presynillin has its aspartates mutated so the first three boxes are normal presynillin molecules expressed in a cell this box shows if you change the one of those presynillin aspartates to any other amino acid it makes no difference which we chose alanine and you drop a beta production by about sixty percent if as one of my graduate students did you take this cell and put in an aspartate mutation in the other form of presynillin called presynillin 2 you drop a beta to zero so what am I telling you here what I'm saying is that presynillin matters to you and me it's the enzyme that you and I have in our brain that does the final cut in APP to liberate the little red box or the so-called abeta peptide that makes up the myriad plaques in the patient's brain and this shows that diagrammatically presynillin has eight transmembrane domains and the two D's are aspartates cut APP which is shown here as if it's lying in a groove in this protein and liberate the part of APP that we call amyloid beta this happens to all of us throughout life so if you have nothing better to do with the next twenty minutes or so you can stay and listen to the rest of the lecture but otherwise you may want to return to the beautiful sunshine outside now it turns out that APP lies in a pore-like structure within presynillin so if the plane of this screen were the wall of a neuron, the outer wall then the orange helices are eight transmembrane helices of presynillin and the white is APP the green are those two aspartate residues and the yellow is a water molecule that needs to cut a substrate so we think this is why a beta is made now why did this arise during evolution in our brains and throughout our bodies it may be explained by the work of Gary Strule and I have a Greenwald at Columbia who showed that in a fly when the fly is normal you get a beautiful clear wing but when the fly has a dysfunctional presynillin molecule you get a notched wing there are big notches here and there are other problems with the fly that I won't talk about this is something that they recognized as a well-known phenomenon the so-called notch phenotype in a fly that is due to dysfunction of a protein called notch why do I tell you all this to show you this diagram presynillin shown in purple winds its way out of the membrane of your brain cells and mine eight times and we have evidence now that it uses these are aspartates within the transmembrane domains to cut the protein called notch liberating this part to the nucleus where it does good things if a fly doesn't have a proper presynillin molecule like if it has an aspartate to alanine mutation it doesn't develop properly and it has a notched wing and dies the trouble with this very useful reaction is that there's another reaction over here in which a different substrate called APP undergoes remarkably similar cutting and the two aspartates liberate the blue box here the amyloid beta so I like to say that you're looking at a diagram of why it is in my view of how all semers are why all semers arose in the human population that because presynillin is critically necessary for notch cleavage in all multicellular animals in flies and worms you had to keep it going throughout life and during development but coming along for the ride were other proteins we know of 20 now that are cut by this mechanism that we've elucidated and one of them is APP it probably didn't matter to you and me when we died when we were supposed to so to speak as we got done with reproduction and saw to it that our children made it through life we live much longer than that and this sticky little fragment of APP can build up in one's brain now I've told you a little bit about the life cycle of A beta as regards production of the protein and how the genes are caught all semers regulate that production if you produce A beta throughout life at 1x but you degrade it to 0.8x it has the possibility of going to aggregate or clumping we've studied the degradation process we can only say one word about that that there's an enzyme called insulin degrading enzyme that we think is one of the main enzymes that uses its active site to break down A beta after it's made and we're looking now for mutations in this IDE gene that might predispose to Alzheimer's and perhaps also to diabetes because it degrades insulin I can answer that question later on I'll tell you a little bit about the aggregation of A beta because you need to ask me well if A beta builds up because of genetic reasons why does that matter what causes trouble with synaptic function we've made an observation recently that A beta which is shown here on a simple gel as a 42 residue protein can form little doublets shown here and quadruplets that are basically aggregates of A beta and we can show this in a very simple cell culture model as you're looking at here the point is that A beta doesn't like to stay by itself too long and after time it finds a partner and makes a 2-some then a 3-some and then a 4-some and we ask the question in living animals what are the consequences of that in this diagram we're able to show that when a rat is given a particular electrical stimulus in its memory center of the brain the hippocampus if it's a normal rat it'll get this dark tracing it has a potentiation of its synaptic energy but if it's first given the medium from the cells I showed in the last slide the blue tracing ensues the animal is unable to maintain long-term potentiation or LTP we've gone on to show that this problem from A beta is not the singlet but the doublet and the triplet and it's also not a whole plat because the material we injected to these rats is devoid of large amyloid clumps we can cancel out this effect here again is this problem maintaining long-term potentiation in the memory center if you co-inject an antibody to A beta you rescue this a living animal and we've done a wonderful collaboration with Jim Cleary and Karen Chalash at the University of Minnesota and they're both in the audience I had the pleasure of having lunch with them today and Jim used his paradigm of training rats to alternate the pressing of two levers changing from lever one to lever two after pressing lever one enough times to get a food pellet and so on it's quite amazing what rats can be taught to do and Jim scores the errors the rat makes as perseveration errors if the rat perseverates or stays on the first lever too long or switches too soon and the rat switches to the wrong lever so you can score this test very sensitively in a living awake rat then what Jim did was to inject the medium of those cells that make doublets and triplets of A beta into the brain ventricle fluid and see what happens to behavior this is what the rats actually have to do in Jim's task press lever A two times then lever B six times lever A 12 times lever B 20 times lever A 30 times each time they get a pellet of food they go up to 56 and then they know how to go back down to two these rats do algebra and the fact is that when you inject telltale amounts of doublets and triplets you get a problem if we inject normal condition medium from cells you get the white symbols which are okay there's no rise in errors but if you inject the medium that contains doublets and triplets and quadruplets you get an error in this form of memory of a learned behavior the error rate goes down after just a day or two the same thing is shown here for injecting the whole medium by the way if we take an antibody and neutralize or remove the A beta material then the symbol is clear that is the animal is okay in its performance we separated the doublets and triplets shown here from the singlets or monomers shown here and injected each of these into rats and got this response just the doublets and triplets of A beta caused the rat to be unable to recall exactly how it should do this test at least on day zero when the material was given by day one the rat was fine but the monomers at much higher level didn't do anything like that so let me summarize what I've told you and lead into the short but important discussion of treatment and prevention the scientific information that I've shared with you leads my colleagues and I to believe that there is a complex series of steps that lead to the dementia of Alzheimer's disease in dominantly inherited forms of Alzheimer's disease mutations of the genes I pointed out APP itself or PS1 or PS2 increase A beta 42 production throughout life and that leads to its accumulation in the brain and its oligomer formation or its doubling up the A beta 42 accumulates as doublets and triplets and there are subtle effects of A beta oligomers and there is a dramatic efficiency so to speak now there is another way that you can get this problem without inheriting these mutations the much more common way is non-dominant forms of Alzheimer's including so called sporadic Alzheimer's in which perhaps failure of clearance of A beta removal of the peptide from the brain leads to the same downstream consequences a gradually rising level of A beta 42 in the brain now that inheriting the April E4 gene which is a normal gene variant leads to this buildup of A beta and maybe IDE and other enzymes could also be a molecular cause downstream is a complex cascade that I haven't explained to you today and we do not understand its details but there is more and more evidence that this kind of set of reactions gradual deposition of A beta 42 as early plaques that appeared in the 12 year old Down's patient and activation of inflammatory cells leads to things like altered neuronal calcium homeostasis oxidative injury and altered kinase activity which are the enzymes that might make the tau into tangles so my view of things is that there is a cascade of events that occur downstream of the buildup of A beta right now we only intervene down here by providing for example drugs like Aracet or Exilon or Remino to increase acetylcholine levels in the brain here is looking at it another way a cartoon the original version of which I drew way back in 1990 but I think is still accurate I didn't draw the actual image that was an artist but I gave him a back of the envelope sketch amyloid beta protein forms over time in your brain early diffuse plaques at that time an axon that happens to be in the vicinity of the plaque may have quite normal architecture and while we surmise this at a time Brad Hyman my colleague at Mass General showed ultimately by ultra structure that that was indeed the case but as time goes on and the plaque becomes more mature A beta forms more chain like structures helper molecules that are really bad helpers come into the fray and microglial cells migrate towards the plaque then the axon in the vicinity is somewhat tortuous as Hyman has shown and perhaps inflamed thus short circuiting the communication between that neuron and this or so we believe now before we get to therapy we have to have a way to see this process in vivo and a wonderful thing has developed in particular Bill Klunk in his colleagues at the University of Pittsburgh have essentially invented a compound called Pittsburgh compound B that can be given to patients and controls and you can help light up the amyloid deposits in the brain or again so it seems again this is cutting edge science and we don't have all the answers but it looks like compared to the conventional way or more conventional way we might distinguish an Alzheimer's from a control brain there is a more black and white signal when you image the amyloid plaques with a dye that can be given to patients safely and go to their brain to image it that would allow us to select patients for therapeutic trials and the therapeutic trials I'm alluding to would address these four targets inhibiting those enzymes that generate a beta which again are called beta secretase or gamma secretase aka presonillin alternatively let A beta be made and prevent its aggregation into these doublets and triplets or promote their clearance and there comes the notion of an A beta vaccine that you may have heard about third you could inhibit the inflammatory process around the amyloid plaques fourth you could interfere with the complex downstream events that are a response to A beta buildup or so the hypothesis predicts now one of these has actually made its way into trials the A beta vaccine and I'll show you a quick example of that this slide comes from the work of Dale Schenck and I have to make a disclaimer the company in which he works Athena Neurosciences I served as the scientific founder of back in 1986 nonetheless this work is his own work and I did not participate in these experiments what Schenck and colleagues showed was that if you treated an animal for six months with saline injections there was plenty of buildup in the mouse's brain of amyloid plaques instead if you immunize the animal with the actual peptide that makes up those plaques A beta you got an immune response that led to some kind of removal of A beta from the brain this has been a robust phenomenon that any number of scientists have reproduced after his observations and this work went on into clinical trials here's one human being who died after a phase one study because of a pulmonary embolus that is for a separate reason and in that phase one study the patient had received the vaccine for about nine months what the pathologist in England described in this one case were these skip areas areas where there were very few or almost no amyloid deposits in contrast to an adjacent area that had them and here again in this part of the brain that's usually affected in Alzheimer's there were only a few microglial cells containing A beta suggesting that in this one case the vaccine had somehow led to a clearance of A beta in the brain now this went into a phase two trial and there was good and bad apparently one of the potentially good effects was that in this study from one of the clinicians who did the trial a man in Zurich, Roger Nitch and colleagues there was a worsening of dementia over 12 months in patients who had no antibody titer and less worsening of their mini mental state exam with an intermediate rise in titer and a lack of worsening when they had a strong rise in anti A beta antibodies as a result of this vaccine and there was less Alzheimer accumulating the bad effect was that 6% of the patients in the trial had a inflammation in the brain none of the patients died from this but the trial was terminated and the patients gradually recovered but had a very bad effect so where does this stand now what's happening now is that a number of basic laboratories have understood why the reaction occurred it was a T cell reaction and different kinds of vaccines have re-entered clinical trials that are unlikely to cause this particular reaction we don't yet know if they'll cause other reactions but one particular trial started in November 2003 and only with such trials will we learn whether this particular approach lowering A beta in the brain will prevent as these early data hint at but certainly do not prove the decline in mental function that occurs with time now I've mentioned some of the people who helped me with this work in particular I mentioned Jim Cleary Karen Chalash there are a number of wonderful scientists work of this sort comes from a joint exercise by dozens or even many tens of scientists in all labs and I've given you a snapshot of the work that I've contributed to over time only time will tell whether this lack of synaptic firing which happens over time in Alzheimer's disease can be rescued through the mechanism that I illustrated my guess is that it will work and that we will slow down the lack of communication between synapses but it will take a lot of hard work for several years at least of clinical trials before we know if this comes to fruition thank you


Bring your own device to Appalachian Wireless and get up to $300 in bill credits. If you're looking to switch to the Big Blue Appalachian Wireless Network, there's no better time than right now to bring in your device, because we are you. We are Appalachian Wireless. On January 25th, Mountain Comprehensive Care Center will be at the Appalachian Wireless Arena to conduct the annual K-Counts survey for homeless individuals and families in the area. The purpose of the survey is to understand where the homeless are living and to help improve their living conditions. There will be a follow-up on the 26th at the Riverbank behind Paintsville City Hall to ensure everyone is accounted for. So on January 25th, we're asking people, where are you sleeping tonight? And on January 26th, there will be where did you sleep last night? We really like that change, because that gives us flexibility to maybe get some people who didn't get counted the night before, and also it's harder to count at night in Eastern Kentucky. We have topographic challenges, and people are not in easily accessed places. While many are still struggling with homelessness following the 2022 floods, Mountain Compa is trying to provide help. It's important to count everyone going without proper living conditions. This count is, like I mentioned before, it's important to capture the accurate number of homeless that we have so that we can get more resources from Congress pointed towards this region, and then that way it will give us more housing resources. It's a direct correlation to rental assistance that is available for us. Anyone who, you know, is homeless, needs resources and wants to participate or wants to participate, they can call our housing office. That number is<PHONE_NUMBER>, and a very nice lady named Kenzie will answer the phone, and she will dispatch someone who, one of our volunteers that is participating to get out there to take, give them a survey, bring a care package, whatever they need. Reporting for Mountain Top News, I'm Nick Column.