Of all those events, and the pathology level, do you know what is the more upstream, meaning, earlier events that you can observe at the cellular level for AD? There are so many changes. What would you expect? Will it be the death of the cell body? Will it be something? But what about cellular changes? If you picture, if you take lot's of Pictures of these Alzheimer's brains and effected areas. You see the neuron cell body, you see the dendrites, you see the axons, you see the synapse and so on and so forth. And you are very diligent. You analyze 4,000 of them and collectively, what would you predict, what would you think that the earliest thing you can distinguish, you can tell, ah-ha. There is a difference between AD brain and a normal, control brain. What would you expect? It takes quite a bit to really kill a neuron, because our cells are very smart and they deal with all these insults, we adapt. But the loss of synapse, is really the earliest one that correlates AD pathology. So far we have observed. It's way before the degeneration of dendrites, axons and of course, it's a way, way before the actual cell death of the cell body. And as a matter of fact, in the field, there is a description like this, on the left hand side, that's a pretty normal looking neuron. With it's cell body, with it's healthy dendritic trees, and with an axon going out. And as it goes from a normal one to it's demise, to it's death, you first lose off these synapse because they are the most outside one. The second one you lose is the axon or dendrites, and it's in the end stage the cell body actually just disappears. And this is, in the history of study, don't take that for granted. There were pretty big debates about what's the process of cell death and are they dying back or dying forward? And it seems,now, our evidences are supporting the quote on quote Dying Back Model. Dying Back means the most distal ones. Actually has abnormalities. They have abnormal transmission or synaptic structure then gradually it dies back. The next question, in general, what are the most common ways or modes of cell death? What are their main features? You have heard a lot about that. Hint, there are mainly two. There are? Speak up, please. >> Apoptosis. >> Apoptosis. >> [INAUDIBLE]. >> There is another one. >> Necrosis. >> Necrosis, very good, thank you. Apoptosis in Chinese, [FOREIGN]. Necrosis, [FOREIGN]. Does anybody remember what's the main feature of necrosis or apoptosis? Seems like you are quite well prepared. Cast space? Good, cast space [FOREIGN]. >> [INAUDIBLE] >> Hint. It's normally in mitochondria, in the intermembrane of space. >> Cytochrome C. >> Cytochrome C. [INAUDIBLE] Very good. Does everybody know how cytochrome C was discovered as a trigger for a apoptosis? The story goes. Xiao Dong was an assistant professor, just starting in Emory. He wants to study apoptosis and the assay, I'm asking the assay, is just plate out cells, use UV light, damage them. And then, after about half an hour, an hour, you can standardize the curve, they are gradually there. Xiao Dong out of doing that just pick those cells at different time points to a hard core bio chemical assay say, what changed? What's going on here, and then the story continues. What it does is, Xiao Dong says okay, let me get the cells that are going through apoptosis. The hypothesis he had was, there's gotta be something that's causing apoptosis. I don't know what it is, but if I shine UV lights to cells and they're gradually dead. Let me have all these cells, and I separate them into fraction number one, fraction number two, and so on so forth, and then the idea is, add this one back to healthy cells, see if they die, add these, these, these, just add them back, see which one gives you an effect and one of them do and he asks, okay if this one can cause cell death, what's in that one? Then you separate into, again, sub fractions, sub fractions. And do the same thing again, again, again, again. And eventually, miracle will happened. He got cytochrome C. Do you know what his colleagues commented when Xiao Dong talked to them? >> [INAUDIBLE]. >> Exactly. Because cytochrome C is not a new protein, we have known cytochrome C for years. His colleague, a big professor, patted on his shoulder and says cytochrome C, congratulations. That's a pink colored protein. [LAUGH] Xiao Dong laugh, but Xiao Dong won't stick to it and just gradually approve prove that it's really the first trigger was cytochrome C for release from mitochondria, then it trigger caspase this, caspase that, and there are many, many modulators. Xiao Dong when for that contribution, it's really, really important, and I truly think it deserves a big price. It's literally the first understanding of that process. That's apoptosis. How about necrosis? Cells die through that. What do they do? What's the features of necrosis? I summarize this comparison of apoptosis versus necrosis here. There are many features at the level of nuclei reaction or the subcellular compartments or the membrane and in a nutshell. [FOREIGN] Apoptosis is much more a controlled program cell death whereas necrosis is like everything [SOUND], just explode. Okay, now, the next question in the context of today's discussion. In AD, we know we have cell death, we have. Do you know what kind of cell death we have an Alzheimer's Disease brain. That's a little bit harder question. But the way I want you to answer that, is not by looking through the literature, just think or make a guess. >> [INAUDIBLE] >> You think apoptosis should be the one? Anybody else? Do we have a counterargument, somebody says I think it's the other way. Okay, then I will be the counter argument. What is your reason of thinking, must be apoptosis, why is that? Her argument is, if you take a look at these, you don't see the typical necrosis, some explosion type of cells. You don't observe that. Very good. Anything else. Apoptosis do you think? I think what your saying is necrosis are usually pretty acute [FOREIGN]. It doesn't look like it's, [FOREIGN]. You guessed, must be a pretty long program cell death. Very good reasoning. Very good reasoning. Now, as your opponent, [FOREIGN], I'm proposing something that will argue against your hypothesis. I have several evidence. First of all, in AD brain, at different stages, because some people died of something else even at early stage. These are precious brain samples. We can take a look. At early stage, middle stage, and late stage, if you cut it and if you stain with lesser caspase and all that, you don't see typical apoptotic cells. [INAUDIBLE] whatever, it's just not there. To make things even worse, in animal models, people have done research, that you knock out apoptotic components and cross that to AD mass models. There is no rescue. That's my argument somehow it doesn't quite fit. And people have taken out several of these key components, and none of them really rescued. Now let me present my side of the story. I said I think it's probably necrosis, because you can see very clear gliosis. Gliosis is pretty much brains quote, unquote, immune response, so that's one, but I will tell you. In the brain slices, you don't see typical necrosis either. That draws us to this slide. You probably cannot believe this, that in AD, after decades of research, with the best people, we still don't know a simple question. What is the cell death mode of AD? We don't know. It sounds almost unthinkable. With all the years, more than 50, 60 years of hardcore research, with hundreds if not thousands of labs in the world with the best post docs professors in school and in pharmaceutical companies. We still don't know what is the cell death mode in Alzheimer's Disease. And the reason there's several fold, the first one is, you can't cut up a human's brain at will. It's just hard. The second one is actually [FOREIGN] alluded to that. It's a slow process. It takes years for these guys to die, so at a certain point, at a snapshot [FOREIGN], you can only pick several cells maybe are dying. You just don't know. And the third one, is more serious that is. From genetics, from animal models, genetic tests of both necrosis or apoptosis. If you cross these most models to AD most models, there's no genetic modifier effect. It means, at this level at least, it's not a factor. That is almost telling us, there might be another type of cell death which is neither typical apoptosis nor typical necrosis. We don't know what it is. It's yet to be identified. Maybe you guys can contribute. Such a simple first order questions, we still don't know. And in disease studies, these kind of things exist a lot. That must be interesting to you, I hope at some point.
