5.2.8 Genes involved in AD

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Del curso dictado por Peking University

Advanced Neurobiology II

55 calificaciones

Peking University

Advanced Neurobiology II

55 calificaciones

Hello everyone! Welcome to advanced neurobiology! Neuroscience is a wonderful branch of science on how our brain perceives the external world, how our brain thinks, how our brain responds to the outside of the world, and how during disease or aging the neuronal connections deteriorate. We’re trying to understand the molecular, cellular nature and the circuitry arrangement of how nervous system works. Through this course, you'll have a comprehensive understanding of basic neuroanatomy, electral signal transduction, movement and several diseases in the nervous system. This advanced neurobiology course is composed of 2 parts (Advanced neurobiology I and Advanced neurobiology Il). They are related to each other on the content but not on scoring or certification, so you can choose either or both. It’s recommended that you take them sequentially and it’s great if you’ve already acquired a basic understanding of biology. Thank you for joining us!

De la lección

Movement and movement disorders I

5.2.1 The ladder-from molecules to animals6:35

5.2.2 Biology and disease—why do we biologists care about diseases?8:59

5.2.3 Why do we care so much about the 10% genetic forms of neurological diseases?12:12

5.2.4 Cellular functions—what are involved in neurological diseases?3:18

5.2.5 Recurring features in neurodegeneration6:59

5.2.6 Anatomic deficits of AD10:46

5.2.7 Cell death in AD14:46

5.2.8 Genes involved in AD8:33

5.2.9 Practice:what’s the situation in ALS?1:18

Conoce a los instructores

Chenjian Li
Professor
School of Life Sciences
Donggen Luo
Research Fellow
School of Life Sciences
Yan Zhang
Professor
School of Life Sciences, Peking University

Now, let's come back to the ones we mentioned before, genes.

We love genes.

These are the ones that we can grab them, and we can pinpoint them.

We can be a little bit certain about them.

Do you remember, what are the genes so far that identified in Alzheimer's disease?

The more certain ones?

Do you remember what they are?

>> [INAUDIBLE] >> Say it again.

>> Alpha-synuclein >> Alpha-synuclein?

>> No, that's a Parkinson's disease 1.

>> Well, actually, Parkinson's also has this 15% overlap with AD, right?

So you're not entirely wrong, but it's not considered an AD gene.

APP, okay, that's a gene, all right?

These four genes are the main ones.

There are several others of minor importance and some are uncertain.

Okay, but these four are basically, everybody agrees that

these are definitely genes whose mutations contribute to Alzheimer's disease.

The first one is APP, okay?

It is the original big protein to be cut, okay?

PS1 PS2, both of them are scissors that cut APP.

ApoE is a very different one.

ApoE was first identified not by Alzheimer's disease research,

instead, it's by cardiovascular research.

It's apolipoprotein type E, and it turns out to be an important

one contributing to late-onset Alzheimer's disease.

The other three are contributing the mutations of that contributes to

early-onset Alzheimer's disease, which is not that typical, okay?

It's a minor component.

So the Alzheimer's disease genes are like that.

And next question.

What pathways are these gene products involved?

What do they do?

I already told you the answer, which is described here.

The APP needs to go somewhere, and there are different ways of cutting it.

So there's three pairs of scissors, and

the beta-secretase, gamma-secretase cause it,

and there is a way to cut it in the toxic form, Abeta 40 and Abeta42.

One of them is toxic and then seems like all hell breaks loose.

ApoE is quite different from this path.

It's a different way, okay?

Now, it seems in this context, three genes and

their gene products, the protein,

are involved in the same process if you count.

APP, PS1, PS2.

PS1, PS2 are cutting APP.

So all three genes from very different family pedigrees,

they have the same problem.

That's a very, very strong evidence, right?

Three independent genetic conclusion,

but they are working in the same pathway, an immediate pathway.

So that's a strong evidence.

And you know what?

That immediately suggests some ways

to intervene to develop tracks.

What therapeutic strategies would you plan?

Knowing APP, PS1, PS2, what would you do if you

have $10 billion in your pockets, and you say,

I want to have my own pharmaceutical company?

I want to cure AD.

What would you do?

Would you contract Professor Lee to try, what?

Okay, so you are assuming that this APP is harmless.

It needs to be cut to generate a toxic fragment, right?

So you are thinking, hey, if I block the scissor, that may work.

Is that your rationale?

>> Yeah because I do not know if ATP has any more functions.

>> Okay, very good question.

APP itself is not toxic, at least.

It needs to be cut to generate the toxic fragrant.

So your thinking is exactly what all the pharmaceutical companies are doing.

Congratulations, you can be a good to those guys.

Very straightforward.

If cutting is needed, block it, that will work.

So PS1, PS2 inhibitors, secretase inhibitors,

are major targets for pharmaceutical companies.

That's true for any In all of the major pharmaceutical companies.

They have tried left and right.

Why so far?

We don't have the drug yet.

Sounds easy, right?

See, it's an enzyme.

[NOISE] Enzymes are best drug targets,

because inhibiting an enzyme is pretty easy.

Activate is a little bit more difficult, because through years of evolution,

our enzymes are quite well-designed to make them more active, it's difficult.

But to destroy, it's not that difficult.

Why don't we have inhibitors yet as a drug?

>> [INAUDIBLE] >> Blood-brain barrier.

Good concern, but yeah,

we design the drugs that just go through the blood-brain barrier, no problem.

Exactly, because proteins, many of them, they don't carry one role.

They actually have several roles.

I, as a secretase, I can cut APP, I can also cut notch, I can cut this and that.

So if you inhibit me, yes,

you rescued the APP part, but what about the notch signaling pathway?

What about the other one?

So all these proteins, they are good targets for Alzheimer's disease,

but the problem is they also serve other roles in other sickening pathways.

That's why we have very efficient inhibitors.

But there are just not good drugs.

Okay, can you design something that's specific for

APP but not for the other one?

That's the biggest challenge that these pharmaceutical companies are facing.

Okay, I need to hurry up.

So by the same token, if you think about APP, that's a target, too.

If you can eliminate APP, that will do the work, right?

So that's the basis for immunotherapy.

The whole idea is to have antibodies fighting and recognizing APP,

somehow destroy them, and see if we can rescue the cell.

Immunotherapy has been one of the hot areas people are pursuing,

and there are some encouraging data, okay?

So that's the pharmaceutical therapeutic developments

based upon our understanding of the disease mechanism.

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