MPBD: Dementia
There are two types of dementia, Alzheimer’s, Aβ1-40 and Aβ1-42 amino acid long one. The
and frontotemporal dementia. Aβ1-42 is mostly related to amyloid plaque
formation since this one is more prone to
Alzheimer’s aggregation.
Alzheimer’s Disease is a progressive
neurodegenerative disease.
• Loss of memory
• Loss of orientation in time and space
• Language difficulties
• Behavioural changes
• Personality changes
There are two types of cascades in
Alzheimer’s. On the left side, you see Amyloid
Beta plaques that are outside of the neurons in
the tissue. On the right side, you see Tau Tau hyperphosphorylation and aggregation
Tangle proteins that are localised in the Normally Tau proteins bind to microtubules
extensions of the neurites. The purple dots are inside the cell to stabilize them. Tau is very
the blood vessels. You can see that the Aβ is dynamic and gets phosphorylated so the protein
also present in, and around these blood can dissociate from the microtubule so a vesicle
vessels. can pass. In disease, Tau becomes
hyperphosphorylated, which leads to the
destabilization of microtubules and Tau
aggregation.
Amyloid cascade hypothesis
Alzheimer’s research
The cause of Aβ is found to be genetic and is also
related to down syndrome. They found that
people with trisomy 21 start very early (40-50)
with Alzheimer’s pathology. Chromosome 21 is
the chromosome where APP is located. There are
also 5 families of EOAD/CAA that have an APP
duplication and are associated with early-onset
Alzheimer’s disease. These defects/mutations in
the DNA are autosomal dominant, and will be
passed on to the children.
This hypothesis postulates that the
neurodegeneration in Alzheimer’s is caused by
abnormal accumulation of Aβ plaques in
various areas of the brain.
Amyloid Precursor Protein (APP) is a
transmembrane protein that is normally These single mutations lead
cleaved by an α-secretase protein. This does To increased levels of Aβ and
not cause Aβ. However, if APP is cleaved by β- An increased ratio of Aβ1-42/
secretase and then by γ-secretase, the amyloid Αβ1-40.
beta is released. This can be in two variants,
, Αβ1-42 in the PDAPP mouse (APP V717F). In The arctic mutation in APP causes a decrease in
this picture, you see the hippocampus of mice. Aβ formation and an increase formation of
You see that over time the protein aggregation protofibrils. These also cause the formation of
increases. oligomers and therefore cause Alzheimer’s
disease.
APOE is one of the genes associated with late-
onset Alzheimer’s disease and has something to
do with the clearance of Aβ and lipid metabolism.
For a study, they looked for protective genetic
factors in Icelandic people over 85 with and
without Alzheimer’s disease and found a
mutation in APP that protects against
Alzheimer’s.
They also found that presenilin mutations
increase the Aβ1-40/Aβ1-42 ratio, which in
turn increases aggregation, and formation of
plaques.
Autosomal dominant forms of Alzheimer’s:
The age of onset is between 30 and 60 years old.
They have mutations in the APP gene,
Presenilin-1 gene, and Presenilin-2 gene.
A knock-out mouse was made to further
investigate the function of presenilin (PS). The Sporadic forms of Alzheimer’s:
PS knock-out died at birth, so the embryo’s The age of onset is around 65 and poses an
where obtained before birth and the neurons increased risk with apolipoprotein E4 isoform.
were cultured in vitro. What was found is that The risk factors for this type of Alzheimer's are
in the wildtype (+/+) the formation of Aβ was age, diet, head trauma, etc.
much higher than in the knock-out (-/-). They
later found out that presenilin is part of the γ- Both types of Alzheimer’s causes an increase in
secretase complex. Aβ.
It is the enzyme
that cleaves Another experiment was done with knock-out
APP to form Aβ. mice, but they do not get Tau tangles. They
discovered that Tau is required for Aβ toxicity.
Amyloid beta first forms oligomers, which are
toxic species. They did a study with Long-Term
Potentiation (LTP) where they gave a high
stimulus to a brain slice to enhance neuron
firing to study learning and memory. They
treated a brain slice with amyloid beta
oligomers and saw that Aβ oligomers inhibit
LTP, which means that it blocks the synaptic
transmission.
There are two types of dementia, Alzheimer’s, Aβ1-40 and Aβ1-42 amino acid long one. The
and frontotemporal dementia. Aβ1-42 is mostly related to amyloid plaque
formation since this one is more prone to
Alzheimer’s aggregation.
Alzheimer’s Disease is a progressive
neurodegenerative disease.
• Loss of memory
• Loss of orientation in time and space
• Language difficulties
• Behavioural changes
• Personality changes
There are two types of cascades in
Alzheimer’s. On the left side, you see Amyloid
Beta plaques that are outside of the neurons in
the tissue. On the right side, you see Tau Tau hyperphosphorylation and aggregation
Tangle proteins that are localised in the Normally Tau proteins bind to microtubules
extensions of the neurites. The purple dots are inside the cell to stabilize them. Tau is very
the blood vessels. You can see that the Aβ is dynamic and gets phosphorylated so the protein
also present in, and around these blood can dissociate from the microtubule so a vesicle
vessels. can pass. In disease, Tau becomes
hyperphosphorylated, which leads to the
destabilization of microtubules and Tau
aggregation.
Amyloid cascade hypothesis
Alzheimer’s research
The cause of Aβ is found to be genetic and is also
related to down syndrome. They found that
people with trisomy 21 start very early (40-50)
with Alzheimer’s pathology. Chromosome 21 is
the chromosome where APP is located. There are
also 5 families of EOAD/CAA that have an APP
duplication and are associated with early-onset
Alzheimer’s disease. These defects/mutations in
the DNA are autosomal dominant, and will be
passed on to the children.
This hypothesis postulates that the
neurodegeneration in Alzheimer’s is caused by
abnormal accumulation of Aβ plaques in
various areas of the brain.
Amyloid Precursor Protein (APP) is a
transmembrane protein that is normally These single mutations lead
cleaved by an α-secretase protein. This does To increased levels of Aβ and
not cause Aβ. However, if APP is cleaved by β- An increased ratio of Aβ1-42/
secretase and then by γ-secretase, the amyloid Αβ1-40.
beta is released. This can be in two variants,
, Αβ1-42 in the PDAPP mouse (APP V717F). In The arctic mutation in APP causes a decrease in
this picture, you see the hippocampus of mice. Aβ formation and an increase formation of
You see that over time the protein aggregation protofibrils. These also cause the formation of
increases. oligomers and therefore cause Alzheimer’s
disease.
APOE is one of the genes associated with late-
onset Alzheimer’s disease and has something to
do with the clearance of Aβ and lipid metabolism.
For a study, they looked for protective genetic
factors in Icelandic people over 85 with and
without Alzheimer’s disease and found a
mutation in APP that protects against
Alzheimer’s.
They also found that presenilin mutations
increase the Aβ1-40/Aβ1-42 ratio, which in
turn increases aggregation, and formation of
plaques.
Autosomal dominant forms of Alzheimer’s:
The age of onset is between 30 and 60 years old.
They have mutations in the APP gene,
Presenilin-1 gene, and Presenilin-2 gene.
A knock-out mouse was made to further
investigate the function of presenilin (PS). The Sporadic forms of Alzheimer’s:
PS knock-out died at birth, so the embryo’s The age of onset is around 65 and poses an
where obtained before birth and the neurons increased risk with apolipoprotein E4 isoform.
were cultured in vitro. What was found is that The risk factors for this type of Alzheimer's are
in the wildtype (+/+) the formation of Aβ was age, diet, head trauma, etc.
much higher than in the knock-out (-/-). They
later found out that presenilin is part of the γ- Both types of Alzheimer’s causes an increase in
secretase complex. Aβ.
It is the enzyme
that cleaves Another experiment was done with knock-out
APP to form Aβ. mice, but they do not get Tau tangles. They
discovered that Tau is required for Aβ toxicity.
Amyloid beta first forms oligomers, which are
toxic species. They did a study with Long-Term
Potentiation (LTP) where they gave a high
stimulus to a brain slice to enhance neuron
firing to study learning and memory. They
treated a brain slice with amyloid beta
oligomers and saw that Aβ oligomers inhibit
LTP, which means that it blocks the synaptic
transmission.
