Now, let's come back to AD. First question, who discovered AD? >> Alzheimer. >> Okay, thank you, [LAUGH] just a test if you're awake. All right, but I don't know if you have seen this photo about this doctor. Alzheimer, the typical old classic type of medical doctor. Alzheimer's disease is the number one disease both in Europe, in the US, and in China, almost all countries. And it's the leading cause of a disability in elderly. It's also one of this biggest consuming factors dragging down family resources and a social medical resources. Now, question. You guys should know this. What is the biggest risk factor of the disease? The single biggest contributing factor of this disease onset is simply age. If you look at the curve. Before a certain age, almost never, you see Alzheimer's Disease. And it climbs up, usually after 65. And by the time you have 85 or 90, the curve just go exponential. Okay. So, genetic factor is an important one, but compared to aging itself, it's minor. Okay. So, the single biggest contributor is aging itself. Okay. What is the most oblivious of observation in terms of free anatomy of this disease? Ah-ha. We talked about the brain anatomy. If you think about the brain and think about a disease patient versus a normal human being control. What comes up to your mind first in terms of disease? Okay, reduction of the whole brain volume. Atrophy, right? We call it atrophy. Good. Anything else? Just look at the brain, you will see it. A lot of holes, and why there are holes? >> Because there are holes. >> Okay, be careful. It's not the holes all over the brain. There is a disease called the spongiform of disease. [FOREIGN] Those are spongy form, this one shrinks, they are enlarged space, but not holes all over the place, okay? But still, yes, that's good. Atrophy, very good, anything else? We talked about the brain, white matter and grey matter. White matter and gray matter, what do they represent? >> [INAUDIBLE] >> Sitting, please, cell bodies and axons. What do you think in Alzheimer's diseased brain, if you take that from a diseased patient? What do you expect? Grey matter versus white matter? >> [INAUDIBLE] >> A reduction in grey matter, because? >> [INAUDIBLE] >> Okay, degeneration of cell bodies. How about white matter? >> I'm sure how. >> Okay, so you're not sure. Anybody else? What do you think will happen to the white matters in the patient who died of Alzheimer's? Would you expect to be normal, or it's reduced, or it's enlarged? What do you think? It will be reduced. Very good, see? It's not that hard. Here's the brain. On the left hand side, it's somebody who died of something else. On the right hand side, it's the Alzheimer's disease brain. You can see, first of all, the whole brain is becoming smaller. A reduction of weight and size, and because of the reduction, these spaces are becoming bigger, right? Yeah, the second one is, as she said, very clear reduction of gray matter. See how thin those gray matters are, those layers? It becomes really thin, right? And the third one, as he says, well, the white matter is probably going to decrease too, which is correct. because when the cell body dies, and those processes are gone with it. So, there is a reduction overall in size, in grey matter, and in white matter. Very nice. Modern imaging technology really is helping us to understand the disease progression. Because in patients, we cannot just open their brains at different time points in good experiments. This is how modern technology is really helping. So, this is a picture, follow-up picture imaging of two human beings. One is control. One is Alzheimer's disease. And if you look at the ventricle, it's small size in normal human beings controls, but much more enlarged in Alzheimer's disease. And for one patient, you can actually follow this patient for many, many years and see how the structure changes. Next question. What is the most obvious observation at the level of histology? So, we looked at anatomy. Without any tools, we can look at it. It's right there. Now, in histology, we probably need a low level microscope maybe. Not so great ones. Just a 10x. 40x at most. What do you expect? Think about Alzheimer's disease. You must have this, this, this. What comes to your mind? >> [INAUDIBLE] >> Your favorite tangos? >> Inside the cells >> Inside the cell. Good. Intracellular. >> [INAUDIBLE] >> Plaques. Okay, good. Very good. Also the cell, extracellular. There's amyloid plaques. [FOREIGN] Inside, you have the neuro fibroid tangles. What are they made of? >> Maybe the [INAUDIBLE]. >> No. >> [INAUDIBLE] >> Yeah? Tau protein, right? So, tau usually it is the tau tangle inside, and the beta amyloid plaques are outside. That doesn't mean that there is no tau outside, and there is no beta inside, it doesn't mean that. But the precipitation, the aggregation It's like that. Very good. So, if you look at low-level, low-grade microscope, this is what you see. You will see tangles, and you will see plaques. To enlarge that, it looks like this. The tau tangles are more intracellular, and the plaques are more extracellular. Okay, that's the histological hallmark of AD. Now, let's continue to ask the question. What is the molecular basis for amyloid plaque, what is it made of? Anybody knows? The plaque. >> Abeta protein. >> Abeta protein, thank you very much. It's called abeta amyloid plaque, all right, so abeta. Abeta, originally, abeta is from a bigger protein called APP, thank you. And APP is being cut this way, cut that way, to generate toxic fragments. Now, toxic fragments are much prone to aggregation, right? And there is a big debate, or discussion still whether the real toxicity comes from the abeta monomer oligomer inside of the cell, or the true killer is the plaque outside of the cell. The debate is still going on. There are evidence supporting both sides. And there are negative evidence argue against each other. Okay? It's very interesting. But suffice to say, abeta fragments are bad in general, and abeta protein it's easy to aggregate. Now, these are the defining characteristics of Alzheimer's Disease. One is you have amyloid plaques, you have tangles, and at the cellular level, if you look at the brain, there's a lot of gliosis and astrocytosis. [FOREIGN] Meaning it's almost like inflammatory response. It's combined called gliosis. Okay? And gliosis is seen in most of the neuron degenerative diseases. The fourth line is, of course, selective neuronal loss, and then synaptic loss, multiple neurotransmitter deficits including acctylcholine, glutamate, so on and so forth. So, these are the pathological characteristics of Alzheimer's Disease.
