Neurodegenerative diseases
Lecture notes
Content
Lecture 1 – Inflammation and MS ........................................................................................................... 2
Lecture 2 – Oligodendrocyte biology relevance to multiple sclerosis ..................................................... 7
Multiple sclerosis ................................................................................................................................. 7
Oligodendrocytes (OLG): development, signaling (role of axons) ..................................................... 10
Lecture 3 – Oligodendrocyte biology relevance to multiple sclerosis ................................................... 14
Summary: mock questions ................................................................................................................ 23
Lecture 4 – Sex differences in AD .......................................................................................................... 24
Lecture 5 – Neurodegeneration and potential therapies ...................................................................... 30
Lecture 6 – Parkinson’s disease ............................................................................................................. 40
Lecture 7 – iPS cells: disease modeling and therapy ............................................................................. 51
Lecture 8 – Topology, neurotoxicity, poly Q and prion diseases............................................................ 59
Lecture 9 – Neuroinflammation ............................................................................................................ 70
Lecture 10 – Potassium channels .......................................................................................................... 82
Oxidative stress – mitochondria dysfunction .................................................................................... 85
1
,The exam is around 13 question, but with sub-questions. Look at the point per question on what you
have to answer.
Lecture 1 – Inflammation and MS
Eat me signals = macrophages, neutrophils (eat other cells, or bacteria).
Peripheral immune tolerance = outside the lymphoid organs, immune control of the T and B cells in
the peripheral.
The cell type that is central there are the Tregs. These are regulatory t cells (they can suppress
overreactive immune responses). There is a rare genetic effect in babies, they are not capable of
making these cells. They have eczema, nail dystrophia, autoimmune endocrinopathies, alopecia
universalis, pemphigoid bullosa, enteritis. This is caused by a defect in the FoxP3. If you don’t have
the transcription factor, then you don’t have the regulatory t cells. The Tregs are present all the time
and they help to finetune and limit immune responses.
Which organ in the body controls the central immune tolerance: Thyroid (schildklier). This is an
endocrine organ. Also the Thymus, t cells come from the thymus. The thymus is a primary lymphoid
organ. The precursors of the t cells come from the bone marrow. Then they travel to the thymus. In
the thymus there is selection for the proper specificity and affinity of the t cells. If its not right then
they get killed. TCR affinity is the t cell receptor (for the b cell its BCR). The TCR recognized 8-12 t cell
receptors. T cells have a clonal receptor. One specificity is one cell. In the thymus its tested for the
right specificity and affinity. If affinity is to high then they die, if its to low they will also die (neglect).
They go through all the organs, but you still need peripheral tolerance.
Location of the thymus: small organ (atrophy during adulthood) near the lungs. You need to select t
cells with the right specificity and affinity, you don’t want it to attack your own body. In the thymus all
antigens of your own body are presented, for example lung-specific antigens. You mimic all the
antigens of your own body in the thymus. This is the selection of the t cells. When they are in the
body, in the periphery, they help to protect against pathogens.
If the t cells survived the thymus you have undifferentiated t cells. The phenomenon here is
functional t helper cell subsets. They come in different subsets and different functions. One and two
are just number, the first two identified. In the past 30 years many more subsets have been identified.
Tregs: from undifferentiated t helper cells you need different cytokine functions (TGF-B1), to get an
Treg. You don’t need to know the names of the transcription factors. All the helper cells have the
surface molecule: CD4 and CD25. The Treg starts producing TGF-B1, this is for immune suppression.
2
,You need different types of immune responses to other pathogens. Th2 is for parasitic worms. But if
its overexpressive then you can get allergy or asthma. Th1 help with the protection against
intracellular pathogens. HIV1: infects positive cells, affects t cells and macrophages. It affects and kills
central cells in the immune response. Its not acquired, because you get it via infection.
Affects the lungs, lives in macrophages: tbc. Name of the bacteria: mycobacterium, tbc.
Th17: this makes lots of IL-17.
Multiple sclerosis
Small yellow cells slide 2: t and b lymphocytes, these are the only cells that have adaptive immunity.
The red blood cells have a fixed diameter.
Monocytes, macrophages, dendritic cells, granulocytes are the innate immune response
(=aangeboren), they are already there when you are conceived. They scavenge (=verslinden) cells, or
small peptides. And they present antigens so the immune response can kick in. The granulocytes
(neutrophils) are the largest population in your body. They are the first to the rescue. Dendritic cells
are peripheral but also in central organs. Macrophages eat pathogens.
CD8 t cells are cytotoxic t cells. They kill. CD stands for a cluster of differentiation. They are molecules
on the surface and they identify the function of cells.
General number of genes: 20.000 – 23.000 genes. We can probably calculate how many CD markers
in total we have.
CD4 are on t-helper cells. CD8 is for killer cells.
PBMC: peripheral blood mono-nuclear cells. Polymorphonuclear: it has one nucleus which changes
shape all the time. People with PBMC have less neutrophils.
Slide 4: in the middle we have a stem cell. Hema = blood, poietic = making of. So hematopoietic =
making of the blood. (Hematopoietic) Stem cells make blood. There are 10-15 different subsets of b
cells. They arise from the common lymphoid progenitor. Then you also have a common progenitor for
the myeloid and t cells. This is the biological reality.
One of the most effective treatment of MS is to kill all b cells. Then the b cells will slowly come back.
Leukocyte (leuko = white, cyte = cell). -itis = inflammation.
3-signal model of t cell activation: dendritic cell phagocytes the pathogen and presents it.
3
, 1. Antigen presentation: small peptides are presented (in blue), receptor on dendritic cell is
called the HLA (human leukocyte antigen). MHC (this one is for all the species; major
histocompatibility (histo = tissue) complex)
2. Co-stimulatory molecules: some increase the response and some help with finetuning.
3. Inflammatory cytokines: small molecules that move other cells.
This is innate immunity. When activating the t cell the acquired immunity starts, but they need each
other.
EXAM!!
In MS the small peptides are derived from the brain. Then you want to limit the response, for
example by blocking the signal(s).
With the t cell receptor we can recognize part of the white stuff and part of the yellow stuff.
MS: this part is referring to co-stimulation.
For allergy and autoimmune you want to limit the response, for cancer and vaccines you want to
upregulate the response.
MS plaques in the brain. Sclerosis: hardening. The sclerosis is near the ventricles. Its not only in the
white matter but also in the cortex. So it’s a disease of both the grey and white matter.
We say it’s an autoimmune disease, but its difficult to prove. The etiology is unknown. Patients have
difficulty with movement, sensation, vision and cognition. The onset is 20-40 years, but children are
also affected. It is occurring more in females, and rising. Around 1.3-1.7 in a thousand develop MS in
the Netherlands.
Four pathological hallmarks in MS (important for exam):
- Inflammation
- Demyelination (myeline breakdown)
- Axonal degeneration (axons that are cut through, or die)
- Atrophy (the brain becomes smaller)
4
Lecture notes
Content
Lecture 1 – Inflammation and MS ........................................................................................................... 2
Lecture 2 – Oligodendrocyte biology relevance to multiple sclerosis ..................................................... 7
Multiple sclerosis ................................................................................................................................. 7
Oligodendrocytes (OLG): development, signaling (role of axons) ..................................................... 10
Lecture 3 – Oligodendrocyte biology relevance to multiple sclerosis ................................................... 14
Summary: mock questions ................................................................................................................ 23
Lecture 4 – Sex differences in AD .......................................................................................................... 24
Lecture 5 – Neurodegeneration and potential therapies ...................................................................... 30
Lecture 6 – Parkinson’s disease ............................................................................................................. 40
Lecture 7 – iPS cells: disease modeling and therapy ............................................................................. 51
Lecture 8 – Topology, neurotoxicity, poly Q and prion diseases............................................................ 59
Lecture 9 – Neuroinflammation ............................................................................................................ 70
Lecture 10 – Potassium channels .......................................................................................................... 82
Oxidative stress – mitochondria dysfunction .................................................................................... 85
1
,The exam is around 13 question, but with sub-questions. Look at the point per question on what you
have to answer.
Lecture 1 – Inflammation and MS
Eat me signals = macrophages, neutrophils (eat other cells, or bacteria).
Peripheral immune tolerance = outside the lymphoid organs, immune control of the T and B cells in
the peripheral.
The cell type that is central there are the Tregs. These are regulatory t cells (they can suppress
overreactive immune responses). There is a rare genetic effect in babies, they are not capable of
making these cells. They have eczema, nail dystrophia, autoimmune endocrinopathies, alopecia
universalis, pemphigoid bullosa, enteritis. This is caused by a defect in the FoxP3. If you don’t have
the transcription factor, then you don’t have the regulatory t cells. The Tregs are present all the time
and they help to finetune and limit immune responses.
Which organ in the body controls the central immune tolerance: Thyroid (schildklier). This is an
endocrine organ. Also the Thymus, t cells come from the thymus. The thymus is a primary lymphoid
organ. The precursors of the t cells come from the bone marrow. Then they travel to the thymus. In
the thymus there is selection for the proper specificity and affinity of the t cells. If its not right then
they get killed. TCR affinity is the t cell receptor (for the b cell its BCR). The TCR recognized 8-12 t cell
receptors. T cells have a clonal receptor. One specificity is one cell. In the thymus its tested for the
right specificity and affinity. If affinity is to high then they die, if its to low they will also die (neglect).
They go through all the organs, but you still need peripheral tolerance.
Location of the thymus: small organ (atrophy during adulthood) near the lungs. You need to select t
cells with the right specificity and affinity, you don’t want it to attack your own body. In the thymus all
antigens of your own body are presented, for example lung-specific antigens. You mimic all the
antigens of your own body in the thymus. This is the selection of the t cells. When they are in the
body, in the periphery, they help to protect against pathogens.
If the t cells survived the thymus you have undifferentiated t cells. The phenomenon here is
functional t helper cell subsets. They come in different subsets and different functions. One and two
are just number, the first two identified. In the past 30 years many more subsets have been identified.
Tregs: from undifferentiated t helper cells you need different cytokine functions (TGF-B1), to get an
Treg. You don’t need to know the names of the transcription factors. All the helper cells have the
surface molecule: CD4 and CD25. The Treg starts producing TGF-B1, this is for immune suppression.
2
,You need different types of immune responses to other pathogens. Th2 is for parasitic worms. But if
its overexpressive then you can get allergy or asthma. Th1 help with the protection against
intracellular pathogens. HIV1: infects positive cells, affects t cells and macrophages. It affects and kills
central cells in the immune response. Its not acquired, because you get it via infection.
Affects the lungs, lives in macrophages: tbc. Name of the bacteria: mycobacterium, tbc.
Th17: this makes lots of IL-17.
Multiple sclerosis
Small yellow cells slide 2: t and b lymphocytes, these are the only cells that have adaptive immunity.
The red blood cells have a fixed diameter.
Monocytes, macrophages, dendritic cells, granulocytes are the innate immune response
(=aangeboren), they are already there when you are conceived. They scavenge (=verslinden) cells, or
small peptides. And they present antigens so the immune response can kick in. The granulocytes
(neutrophils) are the largest population in your body. They are the first to the rescue. Dendritic cells
are peripheral but also in central organs. Macrophages eat pathogens.
CD8 t cells are cytotoxic t cells. They kill. CD stands for a cluster of differentiation. They are molecules
on the surface and they identify the function of cells.
General number of genes: 20.000 – 23.000 genes. We can probably calculate how many CD markers
in total we have.
CD4 are on t-helper cells. CD8 is for killer cells.
PBMC: peripheral blood mono-nuclear cells. Polymorphonuclear: it has one nucleus which changes
shape all the time. People with PBMC have less neutrophils.
Slide 4: in the middle we have a stem cell. Hema = blood, poietic = making of. So hematopoietic =
making of the blood. (Hematopoietic) Stem cells make blood. There are 10-15 different subsets of b
cells. They arise from the common lymphoid progenitor. Then you also have a common progenitor for
the myeloid and t cells. This is the biological reality.
One of the most effective treatment of MS is to kill all b cells. Then the b cells will slowly come back.
Leukocyte (leuko = white, cyte = cell). -itis = inflammation.
3-signal model of t cell activation: dendritic cell phagocytes the pathogen and presents it.
3
, 1. Antigen presentation: small peptides are presented (in blue), receptor on dendritic cell is
called the HLA (human leukocyte antigen). MHC (this one is for all the species; major
histocompatibility (histo = tissue) complex)
2. Co-stimulatory molecules: some increase the response and some help with finetuning.
3. Inflammatory cytokines: small molecules that move other cells.
This is innate immunity. When activating the t cell the acquired immunity starts, but they need each
other.
EXAM!!
In MS the small peptides are derived from the brain. Then you want to limit the response, for
example by blocking the signal(s).
With the t cell receptor we can recognize part of the white stuff and part of the yellow stuff.
MS: this part is referring to co-stimulation.
For allergy and autoimmune you want to limit the response, for cancer and vaccines you want to
upregulate the response.
MS plaques in the brain. Sclerosis: hardening. The sclerosis is near the ventricles. Its not only in the
white matter but also in the cortex. So it’s a disease of both the grey and white matter.
We say it’s an autoimmune disease, but its difficult to prove. The etiology is unknown. Patients have
difficulty with movement, sensation, vision and cognition. The onset is 20-40 years, but children are
also affected. It is occurring more in females, and rising. Around 1.3-1.7 in a thousand develop MS in
the Netherlands.
Four pathological hallmarks in MS (important for exam):
- Inflammation
- Demyelination (myeline breakdown)
- Axonal degeneration (axons that are cut through, or die)
- Atrophy (the brain becomes smaller)
4
