Alzheimer's disease and amyloid beta | Immune system and amyloid beta

Summary

The video explains Alzheimer's disease, a brain disorder affecting millions worldwide. It delves into how the disease disrupts neuron function through the buildup of two proteins: amyloid beta and tau. These proteins damage communication between neurons, leading to cell death. The video also covers the role of the immune system, particularly microglia and astrocytes, in trying to remove these harmful proteins, but often exacerbating inflammation and further neuron damage. The speaker highlights the need for future treatments targeting both protein dysfunction and immune response to combat Alzheimer's effectively.

Takeaways

• 🧠 Alzheimer's disease affects 44 million people worldwide, with 5-6 million in the U.S., and it is a devastating disorder impacting brain function.
• 👪 The speaker has a personal connection to Alzheimer's, as it runs in their family, making them invested in explaining how the disease works.
• 🌳 Neurons in the brain have distinct parts: dendrites (which receive information), axons (which send information), and axon terminals where signals are transmitted to other neurons.
• 🔴 Alzheimer's disease involves two problematic proteins: amyloid beta and tau, which accumulate in neurons and disrupt their function.
• 🐢 Amyloid beta builds up in the neuron’s cell body, slowing down the communication between neurons, while tau tangles cause the collapse of axonal 'superhighways.'
• ⚠️ Over time, the accumulation of these proteins leads to neuron death, and neurons cannot be easily replaced, worsening cognitive decline.
• 🧬 Microglia and astrocytes, immune cells in the brain, try to clean up amyloid beta plaques but eventually contribute to inflammation, which accelerates neuron death.
• 🌡️ Chronic inflammation, potentially triggered by lifestyle factors like diet and exercise, is linked to an increased risk of developing Alzheimer's.
• 🔬 Alzheimer's progression involves both protein malfunction and immune system dysregulation, making it a complex disease with no current cure.
• 📅 Early-onset Alzheimer's (age 50-65) is more related to protein issues, while late-onset Alzheimer's (age 70-80) is likely driven by immune system dysfunction.

Q & A

What is Alzheimer's disease and how many people are affected globally?

Alzheimer's disease is a devastating disorder that affects the brain, causing memory loss and cognitive decline. Currently, 44 million people globally are living with the disease, with about 5-6 million in the United States.

What are the two main proteins involved in Alzheimer's disease?

The two main proteins involved in Alzheimer's disease are amyloid beta and tau. Both proteins become dysfunctional and contribute to the disease's progression.

How does amyloid beta affect neurons in Alzheimer's disease?

Amyloid beta is normally produced by neurons, but in Alzheimer's disease, the neuron produces too much or cannot clear it properly. This leads to amyloid beta accumulation, which slows down the neuron and disrupts its ability to send signals to other neurons.

What role does tau protein play in Alzheimer's disease?

Tau protein is involved in maintaining the structure of the axon, the part of the neuron responsible for transporting signals. In Alzheimer's disease, tau becomes dysfunctional, causing the axon's 'superhighway' to collapse, leading to disrupted communication between neurons.

What happens to the brain's neurons during Alzheimer's disease?

In Alzheimer's disease, neurons first slow down due to amyloid beta accumulation and tau tangles, and eventually die. Once neurons die, they are not replaced, leading to progressive brain degeneration.

How does the immune system respond to Alzheimer's disease?

The immune system, particularly cells like microglia and astrocytes, tries to help by clearing amyloid plaques through phagocytosis. However, over time, the immune system becomes overactive and produces inflammation, which kills even more neurons.

What are amyloid plaques, and why are they harmful?

Amyloid plaques are clumps of amyloid beta proteins that accumulate outside neurons. These plaques trigger immune responses that lead to inflammation and increased neuron death, contributing to the progression of Alzheimer's disease.

What is the synapse, and why is it important in Alzheimer's disease?

The synapse is the tiny space where neurons communicate with each other. In Alzheimer's disease, the buildup of amyloid beta and tau disrupts this communication, leading to slowed signal transmission between neurons.

What is the difference between early-onset and late-onset Alzheimer's disease?

Early-onset Alzheimer's typically occurs between the ages of 50 and 65 and is often related to genetic factors affecting protein production. Late-onset Alzheimer's, occurring between ages 70 and 80, may be more related to immune system dysfunction.

What are some lifestyle factors that may reduce the risk of Alzheimer's disease?

Exercise and a Mediterranean diet rich in healthy fats, such as those found in fish like salmon and olive oil, have been shown to reduce the risk of Alzheimer's disease by lowering inflammation and supporting brain health.

Outlines

00:00

🧠 Understanding Alzheimer's Disease

Alzheimer's is a brain disorder affecting 44 million people worldwide, with 5-6 million in the U.S. The author shares personal experience with the disease, which runs in their family. They explain the disease's impact on neurons—brain cells responsible for communication. Two proteins, amyloid beta and tau, malfunction during Alzheimer's. Amyloid beta accumulates in neurons, slowing their communication, while tau disrupts axon transport, leading to neuronal dysfunction and eventual death.

05:08

⚡ Neuron Communication and Synapses

Neurons communicate through synapses, tiny spaces where signals are passed from one neuron to another. The first neuron, called the presynaptic neuron, sends signals, and the second, the postsynaptic neuron, receives them. This process is disrupted during Alzheimer's when amyloid beta accumulates and tau tangles form, affecting synaptic communication and overall brain function. The breakdown of amyloid precursor protein (APP) is described, where the good scenario involves harmless byproducts, while the bad scenario leads to amyloid beta production and clumping.

10:10

⏳ Slow Development of Alzheimer's and Genetic Factors

Alzheimer's takes decades to develop, usually over 50-80 years, as the process is typically normal but can go wrong over time. Some people develop Alzheimer's earlier due to genetic factors, such as mutations that cause more amyloid beta to form. The neurons don't work alone; they have cellular 'helpers' like astrocytes and microglia. Astrocytes provide energy to neurons, while microglia act as immune cells. During Alzheimer's, microglia become inflamed, contributing to the disease progression.

15:10

🔥 The Role of Immune Cells in Alzheimer's

The immune system's response to Alzheimer's becomes problematic as inflammation increases. Amyloid plaques build up in neurons, activating immune cells like microglia and astrocytes. These cells try to remove the plaques through phagocytosis, but eventually lose their ability to do so, leading to more inflammation and cell death. Microglia and astrocytes contribute to this inflammation by releasing cytokines, which further damage neurons and exacerbate Alzheimer's.

Keywords

💡Alzheimer's Disease

Alzheimer's Disease is a progressive neurodegenerative disorder that affects memory, thinking, and behavior. It is the most common cause of dementia, affecting millions worldwide. In the script, Alzheimer's Disease is described as a 'devastating disorder' that impacts the brain's neurons, leading to a decline in cognitive function. The video aims to educate viewers on how the disease starts and how the immune system responds to it.

💡Neuron

A neuron is a nerve cell that is the fundamental unit of the nervous system, responsible for transmitting information between different parts of the body. The script describes neurons as having distinct regions like dendrites and axons, which are crucial for receiving and sending signals. The health of neurons is directly tied to the development of Alzheimer's Disease, as dysfunction in these cells is central to the condition.

💡Amyloid Beta

Amyloid Beta is a protein fragment that plays a significant role in Alzheimer's Disease. It is produced naturally by neurons but can accumulate abnormally, leading to the formation of amyloid plaques that disrupt neuronal function. The script explains that an overproduction or inability to clear amyloid beta can lead to its accumulation within neurons, slowing them down and contributing to Alzheimer's.

💡Tau

Tau is another protein associated with Alzheimer's Disease. It is normally involved in maintaining the structural integrity of neurons. However, in Alzheimer's, tau becomes hyperphosphorylated, forming neurofibrillary tangles that disrupt the transport along the neuron's axon. The script uses the analogy of a 'super highway' to describe how tau supports the neuron's structure, and its dysfunction leads to the collapse of this highway.

💡Axon Terminals

Axon terminals are the end parts of a neuron's axon, responsible for transmitting signals to other neurons. The script mentions that these terminals are crucial for rapid communication between neurons. In Alzheimer's Disease, the accumulation of amyloid beta at the axon terminals can impede this communication, leading to a slowdown in neuronal activity.

💡Dendrites

Dendrites are branched extensions of a neuron that receive signals from other neurons. They are likened to tree branches in the script, emphasizing their role in receiving information. The health of dendrites is critical, as their dysfunction can impair the neuron's ability to receive signals, which is a key feature of Alzheimer's Disease.

💡Neurotransmitters

Neurotransmitters are chemicals that neurons use to communicate with each other across a synapse. The script explains that during health, neurons communicate rapidly through these chemicals. In Alzheimer's Disease, the disruption caused by amyloid beta and tau proteins can impair this communication, affecting cognitive functions.

💡Synapse

A synapse is a junction between two neurons that allows them to transmit signals to each other. The script describes the synapse as a 'tiny space' between axon terminals and dendrites where communication occurs. The health of synapses is critical for normal brain function, and their disruption in Alzheimer's Disease can lead to cognitive decline.

💡Microglia

Microglia are immune cells of the central nervous system that act as the brain's primary defense against pathogens and are involved in the repair process. The script explains that during Alzheimer's Disease, microglia become inflammatory and contribute to the disease progression by increasing inflammation and potentially killing neurons.

💡Astrocytes

Astrocytes are star-shaped glial cells in the brain that provide support and protection for neurons. The script describes astrocytes as taking care of neurons by storing sugar and providing glucose. In Alzheimer's Disease, astrocytes can become activated and contribute to inflammation, which can further damage neurons.

💡Inflammation

Inflammation is part of the immune response involving cellular reactions to cellular injury or infection. The script discusses how inflammation, particularly from activated microglia and astrocytes, can contribute to neuronal death in Alzheimer's Disease. It also mentions that a lifetime of inflammation might increase the risk of developing the disease.

Highlights

Alzheimer's disease is a devastating disorder that affects 44 million people worldwide, with 5-6 million cases in the U.S.

Alzheimer's runs in the speaker's family, offering a personal connection to the disease.

The brain contains about 86 billion neurons, and Alzheimer's disease impacts the structure and function of these neurons.

Key proteins involved in Alzheimer's include amyloid beta and tau, which play different roles in the disease's progression.

Amyloid beta accumulates in the neuron, slowing down communication and eventually leading to neuron death.

Tau protein becomes dysfunctional in Alzheimer's, collapsing the 'superhighway' (axon) that transports signals within the neuron.

The immune system, particularly microglia and astrocytes, tries to respond to Alzheimer's but ends up contributing to neuronal damage.

Microglia become inflammatory during Alzheimer's, transforming from a resting state to an aggressive, blobby form that causes further damage.

Amyloid plaques form when amyloid beta clumps together, contributing to neuron death and exacerbating the disease.

In early Alzheimer's, the brain’s immune cells (microglia) can help clear amyloid plaques through a process called phagocytosis.

As the disease progresses, the immune system loses its ability to clear amyloid plaques, leading to increased inflammation and neuron death.

Chronic inflammation, triggered by immune cells, is believed to be a key factor in Alzheimer's disease progression.

Cytokines like IL-1 beta and TNF alpha, along with reactive oxygen species (ROS), are common inflammatory molecules found in Alzheimer’s disease.

Lifestyle factors like exercise and a Mediterranean diet rich in healthy fats can reduce the risk of developing Alzheimer's.

The speaker suggests that early-onset Alzheimer's may be more related to protein dysfunction, while late-onset Alzheimer's could be driven by immune system dysfunction.

Transcripts

alzheimer's disease is a devastating

disorder

that affects the brain right now 44

million people in the world

are living with alzheimer's disease and

of that about five to six million of

them are living in the united states

now i know firsthand that this is a

terrible disorder to have it runs in my

family

and i want to give you information to

better understand how alzheimer's starts

and then how the body specifically the

immune system

responds to alzheimer's disease so here

i've drawn for you a neuron

if we could zoom way into the brain you

would see

lots and lots of neurons in fact if you

had enough time to count you could count

86 billion neurons

now you might see that there's some

really distinct regions

in the neuron and i want to explain them

to you because it's going to help you

understand alzheimer's

the top of the neuron you might notice

it looks a little bit like a tree

and if you're really into language you

might know that greek for tree

is dendrite so up here

these are called dendrites

and then there's this long connector

this is called

the axon

and at the bottom the axon ends

and another word for end is terminate so

at the very end here these are called

axon terminals

okay one other thing i want to point out

to you here

is this region around the circle this

circle

is the nucleus where the dna of the

neuron is contained

and around it is called the cell body

so you might be wondering how does a

neuron work basically the dendrites

receive information receive

and the axon terminals send information

okay now that you know what the

dendrites and the axon terminals do

where does alzheimer's happen and the

answer unfortunately is

is everywhere so there's two proteins

that

go awry during alzheimer's disease one

of them is called

amyloid beta

and we're going to talk a lot more about

that and the other one is called

tau i'm going to color code these for

you

so in most of the papers i read i

studied alzheimer's for about

nine years in most of the papers i read

amyloid beta ends up being red so

i can't help it but here amyloid beta

actually is produced by the neuron

during health

over time the neuron produces too much

amyloid

or loses the ability to clear it with

the help of other cells of the brain

and what that means is it starts to

accumulate

inside the cell body of the neuron

and when this happens the neuron starts

to slow down

it can't do what it normally wants to do

which is to communicate

signals to other neurons in your brain

that are all connected

to a thought or a memory or a sensation

so once amyloid beta starts to gunk up

the cell body

the neuron slows down it can also start

to gunk up the axon terminals here

and that means that this neuron is not

going to be able to send

signals rapidly to other neurons

that they're connected to tau works a

little bit differently

tau is more to do with the axon

the axon is really like a super highway

so it can take anything from the cell

body

all the way down to the axon terminals

in fact the longest axon in your body is

approximately two to three feet

depending on your height one that

reaches from the base of your spinal

cord all the way down to your foot

but see normally tau is supporting the

highway

like cement pillars if you could imagine

the highway sort of

supported in midair so if tau ever gets

disrupted

it's like somebody took out all of those

pillars and

the highway collapses so then there's

no transport from the cell body

to the axon terminals

so between amyloid beta and tau

the neuron initially is slowed

so first off communication is slowed

and then secondarily the neuron will die

now as we age we don't replace

the neurons in our brain at a very high

rate

meaning that most of the neurons that

are lost during alzheimer's disease

cannot be recovered with any of the

techniques we have available

all right so let's add some details here

we have neuron 1

in gray and it's communicating with

neuron 2.

now you might have noticed two features

from before there's gray

axon terminals and they're right next to

the blue

dendrites from neuron 2. so there's a

tiny tiny space

between the axon terminals and the

dendrites

that's actually called the synapse it's

a very special space

where neurons can communicate with each

other

and usually they communicate through

chemicals they can communicate

electrically but they have to be

physically touching then

so neuron one actually has a technical

name it's called the pre-synaptic

neuron

and then there's the second neuron is

postsynaptic

it's literally just indicating what's

happening before and after the synapse

which is the most

important part

all right so here at the synapse

neuron 1 is going to tell neuron 2

to pass along a signal to a different

part of your brain

and during health this happens

incredibly rapidly

and they would be connected together and

working in sync

during alzheimer's disease those two

proteins we talked about are going to

start to build up

and i didn't have enough room before to

draw what it would look like in greater

detail

so here we go

there's lots of little vesicles in all

of your cells

usually good things are happening in

vesicles like recycling

but sometimes bad things are happening

in vesicles

now i don't have an animator so here we

go

it's just like we're zooming in on what

i just drew

this is one of those vesicles in the

blue neuron

and here in pink is a large protein

it's actually called amyloid precursor

protein

and it sounds like it's going to turn

into amyloid beta

all right so amyloid precursor

protein is in vesicles it can be

cut by other proteins in the body two

different ways

one is good one is bad so

let's do the good scenario first

proteins are amazing they have all sorts

of functions

and one of the things they can do is act

like scissors

so here in purple i'm showing the good

scenario

there can be proteins like alpha

secretase that come along

and encounter amyloid precursor protein

and they cut it in such a way

that it turns into a really small

harmless piece

of the protein these typically

don't stick together or clump together

and so they're safe for the brain

so here alpha secretase

now the bad scenario a different protein

comes along

you'll notice based on the color coding

that we're in trouble

this is actually called beta secretase

so yes lots and lots of greek letters

beta secretase cuts amyloid precursor

protein

into amyloid beta

now a little bit of amyloid beta is fine

in fact there's some evidence that it

helps

the axon terminals develop and

potentially even function

but if we make too much it's going to

start

clumping together and that's where the

trouble starts

so if mla beta here is produced at a low

level

you're fine if it's produced at a high

level it starts to clump together

and the neuron can't break it down or

pull it apart

so that's why it takes 50 to 80 years

for this to develop because typically

this process is normal

and helpful there are different types of

mutations that cause people to create

more or even have like a more active

beta secretase

so there are genetic reasons why some

people in certain families

can get alzheimer's disease at an

earlier age

okay now it's time for the rest of the

story the neurons in your brain

are not alone they have a few cellular

friends

now one of which is the astrocyte

astrocytes actually take care of neurons

if you have ever skipped a meal

astrocytes

can actually store sugar for you

in the form of glycogen and then break

it down

and give you glucose just like if your

mom

had a candy bar for you in her purse

astrocytes can take care of the neurons

during health

there's also microglia

now you might see here that the

microglia actually have these long

beautiful branches just like neurons

but during alzheimer's disease they're

not in this beautiful resting state

they actually become inflammatory

and when they're inflamed they look

completely different

they actually have more of this blobby

shape

and when they do that when they change

shapes

the microglia are actually going to be

contributing to alzheimer's disease

all right there are another cell type

called oligodendrocytes but they're not

important during alzheimer's disease

um however they're very important during

multiple sclerosis so you might see them

come up in a video or two

all right so what happens i told you how

those enzymes basically take amyloid

precursor protein

and they start to break it down into

amyloid beta and it's clumping

so this poor neuron here in blue it

basically starts to fill up with amyloid

and then remember i told you that the

tau tangles

are actually going to start collapsing

the super

highway between the cell body and the

axon terminals

so tau is getting tangled up in here in

the axon

and then amyloid is getting tangled up

in the cell body

as well as down here at the axon

terminals

where communication is happening

so over time this neuron is going to die

and the neuron can die from just the

proteins alone

so the amyloid beta or the tau tangles

but what usually happens is that the

immune system

tries to help out and ends up killing

more neurons

so once this neuron dies or even during

the process of its death

you've probably heard of amyloid plaques

being the main issue in alzheimer's

disease

and that's because the disease has

progressed to a certain point

where neurons have died or considerable

amyloid

has been exocytosed or basically

trafficked outside of the neuron

now these clumps these tangles are

sensed by your immune cells both

microglia

and astrocytes now they can clean these

up a little bit

during the early stages of disease

microglia can remove these

through a process called phagocytosis or

cell eating

but then over time microbial lose the

ability

to remove these plaques all right

so then once these have been sensed if

you really are

like deep in the weeds of alzheimer's

disease these are sensed with

receptors on the outside of the immune

cells particularly

toll like receptor 4

that very commonly is used to bind and

identify

amyloid plaques let's just write that

out for you

and now the microglia and the astrocytes

begin to produce

inflammation

there is some evidence that an

increased lifetime of inflammation

will lead to alzheimer's disease which

is why

there are some studies showing

that exercise and eating a mediterranean

diet full of

fish like salmon or olive oil

things that have good healthy fats

actually reduce

your lifetime incidence your risk

basically

of getting alzheimer's disease so now

your immune cells are making

inflammation

inflammation are basically called

cytokines

and they're small proteins that allow

immune cells to talk to one another

and if you want some specifics common

ones found in alzheimer's disease

are il1 beta tnf alpha

and something called reactive oxygen

species or ros for short

not rodents of unusual size okay

astrocytes are pretty much doing the

same thing

now when the neurons in this general

vicinity

encounter these cytokines they can be

asked to undergo apoptosis

or cell death so here

microglia and astrocytes combined

are going to increase the cell death

of neurons anywhere near

these amyloid plaques so amyloid plaques

lead to astrocyte and microglia

activation

inflammation this inflammation is going

to start to kill

these neurons right here it can also

sometimes

increase the amount of amyloid plaques

being formed i hope that explains a bit

more about alzheimer's disease and how

it works

basically it's amyloid beta protein and

tau protein

becoming dysfunctional and dysregulated

and stopping the neuron from

functioning properly at a cellular level

and then the neurons can die

and in the process of making those

proteins and in the process of dying

the neurons activate the immune cells of

the brain

microglia and astrocytes and although

they help in the beginning of

alzheimer's disease

by removing plaques towards the end of

alzheimer's disease

they end up contributing to inflammation

and then the inflammation kills even

more neurons and you're just stuck in

this terrible loop

and right now there are no drugs to

treat that neither to treat the

underlying protein issues

nor the immune cell dysfunction

so i think that's what needs to be

focused on in future is alzheimer's

disease

truly a disease of protein dysfunction

or is it truly a disease of the immune

system

there's really evidence for both i think

that in people

who have alzheimer's disease happening

early onset so that means between about

the age of

50 and 65 those people probably have

more of a true

protein issue and people who are

diagnosed later in life so between 70

and 80

those people probably have more of an

immune cell issue and as long as we

could come up with a way to boost

microglia and astrazite function that

might be more appropriate

treatment for people with late-onset

alzheimer's disease

if you have any more questions about

alzheimer's disease or other

neurodegenerative diseases

please drop them in the comments section

and i will have more videos

on neuroimmune diseases in the future

because that's primarily what i study

alright stay healthy bye