Alzheimer's disease and amyloid beta | Immune system and amyloid beta
Summary
TLDRThe 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
🧠 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.
⚡ 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.
⏳ 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.
🔥 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.
Mindmap
Keywords
💡Alzheimer's Disease
💡Neuron
💡Amyloid Beta
💡Tau
💡Axon Terminals
💡Dendrites
💡Neurotransmitters
💡Synapse
💡Microglia
💡Astrocytes
💡Inflammation
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
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