Are Infections Causing Alzheimer's Disease? | Robert Moir | TEDxCambridgeSalon

[Applause] so a first person to be diagnosed with Alzheimer's disease was August dieter in 1906 and when asked a question she had often reply oh god I've lost myself I have lost myself so 100 years later that remains one of the most poignant and eloquent descriptions of what it means to have this terrible disease and the statistics for Alzheimer's disease often called AD a truly frightening if you're expecting to celebrate your 85th birthday you've got a nearly 50% chance that you'll be among the 14 million Americans that are expected to have the disease by 2050 and looking after you and your fellow ad sufferers is going to top one trillion dollars and it's not just the monetary cost it's the terrible burden and the emotional price that has to be paid by the people that look after a dig patients and their families so I think an old Australian poster actually captures this very well that is August Duta and this is that poster it's an elderly lady sitting alone and it says she has Alzheimer's disease and then off to the side or a family and it says and they also suffer from I'm going to share with you some new and surprising findings that are coming out of our laboratory that may help us understand the origins of terrible disease but first what is our Samus disease what did Alice Alzheimer see when he first looked down his microscope in 1906 well the first thing he saw when he did unaided visual examination was a dramatically shrunken blind but it was when he looked down his microscope that he saw the pathological Telltale's that were to define the disease that was to bear his name and the first thing he saw outside of cells were massive deposits of something that he named amyloid and on closer inspection these amyloid deposits resolved into structures with distinct morphological characteristics and he called those amyloid plaques second inside of cells he saw thin thread-like structures called neurofibrillary tangles so neurofibrillary tangles are found in a lot of neurological diseases but huge accumulation of amyloid plaques is specific for Alzheimer's disease and that's kind of how it stayed for the next 78 years it wasn't clear what amyloid was made of it wasn't clear why they accumulated in such extraordinary abundance in AD brain but then in 1984 came a seminal paper that showed that amyloid plaques were made from a little protein called a beta and a beta can self-organize into long thin structures called amyloid fibrils and it's these amyloid fibrils a tangled mass that actually makes an amyloid plaque visually think a microscopic all of fishing line and those fibrils inside that tangled ball are all made of neatly stacked molecules of a beta so in addition we now know that the deposition of amyloid plaques triggers series of pathological events including your February tangle formation that ends with massive brain cell death this is called the amyloid cascade model of Alzheimer's disease and 85% of all drug development programs have tried to stop the amyloid cascade by targeting a beta there's been over 480 clinical trials testing some 250 compounds but as yet not a single one has emerged as able to slow the progression of this disease arguably this is the worst performance in modern biomedical history some of the drugs failed simply because they are unable to modify a beta but a few did achieve they've Pharma logical objective but still they failed to slow the disease's progression we believe some of the reason for the failure of these therapeutic approaches is that there is a complete lack of understanding and knowledge about what the normal role of a beta in brain is and why it forms fibrils and the epiphany for us came when we encountered another little protein called ll 37 and ll 37 and a beta share many important similarities but ll 37 isn't like a beta viewed as of pathological protein the ability of a beta to form fibrils is viewed as a accident of its chemistry the a-beta protein itself is viewed as a piece of metabolic junk with an abnormal stickiness that causes it to form clumps that clump together into ever bigger masses and eventually result in amyloid fibril and essentially amyloid plaques are viewed as an accident of a beta chemistry and the animal and the a beta protein itself as an intrinsic bad player and it's misbehaviors of the root cause of Alzheimer's disease but ll 37 also forms fibrous but it's not viewed as a bad player and that's because ll 37 is a member of a family of proteins called antimicrobial peptides a MPs and a MPs are natural antibiotics and their function is to protect us against infection there the foot soldiers of innate immunity the ancient arm of our immune system and they're particularly important in brain because brain has evolved to exclude antibodies and other rough play players in immunity that could damage their delicate structures so one of the first things we did was an experiment to test whether a beta has antimicrobial activity and this is a classic antibiotic Si and the absence of a microbial growth button confirms that a beta does indeed have any microbial activity very potent ones in fact for some pathogens a beta turned out to be a hundred times more potent than penicillin but the really interesting thing and the thing most relevant for our sinus disease is how it does it because microbes are captured and killed by amyloid fibrils and what I'm going to show you into that next is the model that we've worked out in the last seven years of how a beta protects the brain from infection and the consequence of that which is the deposition of amyloid plaques so the first step in this process is the binding of clumps of amyloid a beta to the surface of microbial cell in this case yeast cells that binding triggers the fib realization which is the formation of an amyloid fibril and the fibril shoots out from the surface of the microbe that growing fibril and the clumps of a beta on the surface of the microbe prevent the pathogen from attaching to our host cells and if it can't attach to ourselves it can't infect us and an unattached microbial cell is highly vulnerable and those growing fibrils eventually tangle up around it and pull it in into a compact structure called an agglutinative and in that agglutinate the pathogens are effectively neutralized at least temporarily you can actually see this happening down the microscope and what I'm going to show you next is a figure from a experiment where we added pathogenic yeast cells Candida albicans to human host cells growing in cell culture and normally the yeast cells go straight down attached to the host cells penetrate it and kill them but if those host cells secrete a beta into the media then that doesn't happen because they never get a chance so this figure shows the Candida's which are the dark shadows and you can see between the long thin lines which are actually the a beta fibrils and then analogy I drew to a fishing line earlier on actually not that far from the mark because like fishing line hooking a fish the amyloid fibrils the microbes and slowly they reel them in and they pull them down into this and a gluten apron but a betas jobs not done there because microbes gonna escape from agglutinates so at that point in this compact type mass of fibrils and microbes a betas killing activities come to the fore to turn that a gluten ate into a microbial killing ground and the first thing it does is the fibrils form pores in the surface of the microbe essentially holes that allow the contents of the cell to leak out the bug bleeds to death this is a classical EMP mechanism for killing microbes but that's not obeyed as only trick so one of five reforms from a beta the proteins ability and affinity for copper ions goes up a billion fold so what that means is that the aggregate the agglutinate draws in copper ions from the brain milieu and a beta uses that metal to catalyze chemical reactions that produces hyper chloride ion better known as bleach the bleach sterile hoses the aggregate but it also does something else at the high levels that are generated inside that a gluten a it causes amyloid fibrils to fuse in a process called cross-linking and that has two effects the first one is to close down a betas ability to generate more hydrogen peroxide which is a good thing if it was to keep going it would damage the surrounding brain tissues but the second thing it does is that it makes amyloid fibrils highly resistant to enzymic degradation and that's important because the microbes secrete a whole bunch of different enzymes whose function is to degrade the fibrils and allow them to escape so they're permanently entombed unfortunately it also means that the brains housekeeping cells have a very hard time removing a beta and the microbial agglutinate which is why some of these plaques could be in your brain for 10 20 30 years so as this next image shows this process is very effective at killing the trapped microbes this is a picture of Salmonella bacteria entrapped in an aggregate and a glutamate and you can see that the cells look deflated and wrinkled they deflated just like a punctured football and their surfaces are highly damaged from the bleach so this works really well this whole pathway protects the brain from infection but the downside is these aggregates accrue in the brain and they end up being amyloid plaques and this is a picture from an outsider diseased brain of a mouse that was infected with herpes simplex one virus three weeks earlier and you can see that you don't have to be in Europe ethology to see that the virus and fibril structure generated looks a lot like this the same thing Alisal time I saw when he peered down his microscope over 100 years ago this model of how a betas fights infection is a rational framework on which the apparently diverse and often bizarre activities that have emerged for about a beta can be rationally understood it also reveals why a lot of the drug trials didn't have much chance of working that targeted some of these but for most non scientists the explanation of a boaters behaviour is a little esoteric the most interesting and significant implication of our work for most people is this if a beta is an antimicrobial peptide clark's are generated in response to a new pathogens is alzheimer's disease caused by a chronic brain infection and our results do suggest that but I would caution against concluding this is the smoking gun for infection causing Alzheimer's disease there's a lot of inappropriate innate immune responses out there and some of them involve the targeting of infections that aren't actually there and AD may turn out to be one of them nonetheless I have to say that the idea that infection can cause that's homeless disease is not as outlandish or as novel as you might expect the first guy to suggest infection is linked to Alzheimer's disease our loss Alzheimer and in fact before the bad player a beta model it was a widely held belief but now the current models you don't need infection to explain out sinus disease because if you've got bad player beta whose behaviors produce Alzheimer's disease it explains it all there is a small but dedicated group of scientists that have painstakingly assembled over decades an impressive and convincing body of data that suggests that infection is linked to out sinus disease and that data along with their own findings really is causing a sea change in a way this disease is viewed and that has led to the consideration of anti-infective as treatments for a D and an explosion of interest in innate immunity as potential pathways that can be targeted by drugs so while the early promise of a better targeting drug seems to be fading there's lots of reasons to be optimistic and as an emerging consensus that imagine bullet single magic bullet is not going to work you're probably going to need multiple drugs at different stages of the disease what we're calling the 3 R's right time right place and right treatment but right now progress on those new ideas is a lot slower than it could be and a lot slower than it should be and the reason is that ad research is cash constraint for every dollar spent on outs honors disease care less than half of one penny is spent on ad research and in 2018 well that funding level is actually three or four times what it has been for most of the last 20 years it's still well below the level of other major diseases our lab has been very fortunate we are one of the few labs with the resources to be able to pursue these new and novel ideas but for most labs that's not the case we're funded by foundations like the cure Alzheimer's fund and good ventures that are organized around a venture capital model of philanthropy and they seek out and invest in high-risk projects that also have the potential for higher returns not in money but in knowledge but for most AD researchers the vast majority they rely on federal grants and the federal grants available at the moment are just insufficient to support the exploration of these ideas in the way that they need to be done and it has to be said we if had if we had not got this alternative funding I would not be here talking about these discoveries today and it also has to be said that these discoveries they should have been made 15 years ago what we've lost because of underfunding we'll never know but you got to think where would be read right now in terms of a cure if we've got the funding we've needed in the last 20 years and where will we be if we don't get the funding in the next it's very frustrating and if we were to take 9 2018 funding and increase it tenfold and sustain that for 20 years and that managed to advance our progress towards a cure just one year just 12 months it would pay for itself and more than that that year would save the lives of more Americans than were killed in the second world war in every war since so funding for Alzheimer's disease is administrated by the National Institute of Health NIH but the budget is set by Congress which brings me to advocacy so the role of advocacy in the development of effective treatments for HIV is a is a resounding example of of collective determination and the power of persistent public pressure but a death patients ad sufferers can't advocate for themselves as as August data said I have lost myself I have lost myself it's up to us to ever get for them and I'd add it's not that we're just advocating for them we're advocating for us well because if you remember back to that 85th birthday statistic if you're planning if you and your partner are planning to celebrate your 85th birthday there's a very good chance that you're going to do it the rest of a lifetime of shared memories so I don't want to be all gloomy and doomy here at the end because it isn't like that the science has never looked brighter but this disease has killed millions and it will kill more and more and more millions if we can't pull together as a nation and confront what is a modern skirt that's stealing our loved ones [Applause] [Music] you [Music]

Channel: TEDx Talks

Views: 3,674

Rating: 4.9298244 out of 5

Keywords: TEDxTalks, English, Health, Aging, Bacteria, Big problems, Biology, Biotech, Brain, Cells, Chemistry, Disease, Elderly, Epidemiology, Evolution, Illness, Medicine, Memory, Neurology, Public health

Id: YkkAk_YA8O0

Length: 23min 20sec (1400 seconds)

Published: Wed Dec 12 2018