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3.3.2 Alzheimer’s disease: pathology

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Advanced Neurobiology I

Université de Pékin

3.9 (279 notes) | 29K étudiants inscrits

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 II, and the latter will be online later). They are related to each other on the content but separate on scoring and 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!

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3.9 (279 notes)

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SB

Jul 27, 2018

This was a true challenge and magically eye opening!

MS

May 20, 2018

I really enjoyed this. The lectures were excellent.

À partir de la leçon

Cellular and Molecular Biology of the Neuron

Let‘s continue with the neuron.

3.3.1 Alzheimer’s disease: introduction and myths15:02

3.3.2 Alzheimer’s disease: pathology7:36

3.3.3 Parkinson’s disease: introduction0:52

3.3.4 Parkinson’s disease: symptoms and prognosis9:47

3.3.5 Parkinson’s disease: pathology3:12

3.3.6 Parkinson’s disease: treatment15:36

3.3.7 Prion diseases14:21

Enseigné par

Yan Zhang
Professor
Yulong Li
Research Fellow

Transcription

And as was said, the pathological hall markers

of this disease is one neurofibrillary tangle inside the cell and

the other one is amyloid plaque or in another way called senile plaque.

So because there are three pathological hall-markers of this disease,

then we have three major hypotheses in this disease.

The Tau hypothesis states the Tau mutation is the cause,

is the original cause of the disease and then the other symptom,

neuronal loss and then deposition of amyloidal beta

are both the consequence of this Tau mutation.

And then A-beta hypothesis stating the A-beta

is the primary cause of the disease and

then the aggravation of tau and the neural loss

are the consequence of A-beta aggregation.

And then we have a cell death hypothesis.

Cell death hypothesis says that synaptic and

neuronal loss is the primary cause of the disease and then

the aggregation of tau and A-beta are the consequence of synaptic and neuron loss.

So let's look at the A-beta hypothesis more closely.

So this is in the senile plaque or called amyloid plaque and

then these are the small molecule of amyloid beta to form these big aggregates.

So the senile plaques are extracellular aggregates of this amyloid peptide.

Besides humans, the senile plaque,

the SP are also found in some chimpanzees,

dogs, cats, and the polar bear.

I always wonder how this study

[LAUGH] was done on polar bears.

The common rats or mice we used in our lab,

they do not naturally have accumulation of amyloid with age.

The precursor protein, amyloid beta, amyloid precursor protein,

is a single transmembrane protein.

It has several isoforms and in the brain, the most common isoform is APP695.

So this protein normally under physiological conditions

is highly expressed in our neurons and in brain region.

And it get modified, it get synthesized in yar and

modified in Golgi and

its final destination is the cell membrane and

it can be located either in cell body or in axon.

And then, we still don't quite understand the normal function or

physiological function of this protein.

Why our neuron axon cells produce so much of APP, every day.

There is some evidence suggest this protein can have function,

or can have a role in neuron upgrowth and extension.

Axon guidance and probably is synaptic

transmission and maintenance of the axon.

The phenotype of these mice are quite mild.

So this is this protein.

The great part is a transmembering domain and

then the N terminus towards the extracellular parts and

the C terminus towards the intercellular part.

And what we see, the amyloid beta peptide is the green part here,

it's when this protein get cut, get cleaved by both

beta-secretase and gamma-secretase here, and

then produce this fragment with around 40 amino acids.

So normally, this protein is not cut by beta and gamma secretase.

Normally, it is processed by so-called alpha secretase.

The size of alpha secretase cleavage is right in the middle of this peptide.

If this precursor protein is cut by alpha secretase around here,

it will not cause Alzheimer's disease.

If it cut by beta and gamma secretase, produces A-beta and

then it has a potential to induce Alzheimer's disease.

It doesn't mean if you have this peptide, this A-beta,

you are doomed to have Alzheimer's disease.

Like in normally aged person's brain, we still have huge

amount of this A-beta peptide, and we don't understand why.

We have this peptide, and some people can have the disease and some people don't.

So the beta and the gamma secretase are the two secretases to

produce A-beta peptide, and then for the gamma secretase.

Gamma secretase is not a single protein,

it forms a complex by presenilin 1, Nicastrim,

Aph-1, and Pen-2 to cut inside of the membrane.

So if you look at this gamma secretase site, its very conspicuous because it cut

inside of the cell membrane and then we know for

most enzyme to have a cleavage, they need to be in the water phase

because they need water molecule into the complex.

But this complex, this enzyme complex located

right inside of the cell membrane.

So this is a diagram showing the structure,

the rough structure of a prison 91,

the major component of gamma secretase complex.

Its a protein with metabole transmembrane domain.

And then with both intermix and

then towards the cytosol region.

And then the yellow part here are suggested to have

the enzyme activity and somatic activity.

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