Lecture neurodegenerative disorders 3: Frontotemporal dementia

Question 1

What is the definition of dementia?

Answer 1

• Interferes with work/personal life
• Decline of functioning
• Not explained by delirium or major psychiatric disorder
• Based on (family) history and objective cognitive testing
• Involvement of at least 2 of the 5 domains → memory, executive skills, visuospatial skills, language, behaviour

Question 2

Vascular dementia, Parkinson’s, Alzheimer’s, Frontotemporal dementia and Lewy body dementia are different causes of dementia. Name the three biggest causes of dementia under 65 years old.

Answer 2

1. Alzheimer’s disease (34%)
2. Other (19%)
3. Frontotemporal dementia (18%)

Question 3

Vascular dementia, Parkinson’s, Alzheimer’s, Frontotemporal dementia and Lewy body dementia are different causes of dementia. Name the three biggest causes of dementia above 65 years old.

Answer 3

1. Alzheimer’s disease (42%)
2. Vascular dementia (32%)
3. Other/Lewy body disease (10%)

Question 4

There are different variants of frontotemporal dementia, either based on a social or language domain (non-fluent or fluent). Name the different variants of frontotemporal dementia.

Answer 4

• bvFTD → behavioral FTD
• naPPA → nonfluent/agrammatic FTD
• lvPPA → logopenic (trouble thinking of the words they want to say
• svPPA → semantic (inable to match words with their meaning)

Question 5

So on what domains is their usually progressive deterioration in frontotemporal dementia?

Answer 5

• Personality
• Behaviour
• Language

Question 6

What are clinical criteria of the behavioural type of FTD?

Answer 6

For diagnosis you have to have at least 3 of the 6 symptoms:

1. disinhibited behaviour
2. apathy
3. Loss of sympathy/empathy
4. Perseverative/compulsive behaviour
5. Hyperorality and/or changed eating behaviour
6. Neuropsychological profile → executive dysfunction, where memory and visuo-spatial functions are relatively spared.

Question 7

What is specific for Alzheimer’s but not for FTD?

Answer 7

Hippocampal atrophy

Question 8

What is specific for FTD but not for AD??

Answer 8

Frontotemporal atropy

Question 9

Is there one specific aggregate/inclusion that is typical or specific for FTD?

Answer 9

No, FTD “comes in different flavours”. Meaning that inclusions like Tau can be prevalent, but also TDP-43 and other inclusions. But Tau and TDP-43 are not specific for FTD and are also prevalent in other disease like AD or ALS.

Question 10

On this picture, ubiquitin staining is used. What inclusions are visualized by ubiquitin staining here?

Answer 10

Tau-inclusions

Question 11

What can be concluded based on this table?

Answer 11

That mutated tau correlates with FTD pathology, as tau mutations are found in FTD-patients. Genetic variants of FTD are often associated with Parkinsonsm and motor neuron diseases (PMD).

Question 12

Also discussed in previous deck: how are Tau-aggregates formed?

Answer 12

When tau is hyperphosphorylated. This causes them to detach from microtubuli. Tau is now able to aggregate and can no longer stabilize microtubuli, causing unstable microtubuli.

Question 13

Here, a picture is displayed of the tau gene. What region/domain is responsible for the binding of microtubules?

Answer 13

The four repeat domains

Question 14

Six isoforms of the tau gene exist, created by differential splicing. What consequence do thise isoforms have for (possible) aggregation?

Answer 14

Some of these isoforms have 3 domain repeats and some have 4. The isoform with only 3 domain repeats is expected to bind less well to microtubules and therefore is expected to tend to aggregate faster.

Question 15

As can also be seen here, some isoforms all have 3 repeats. To identify different isoforms, western blot can be used. Only this is not immediately possible. Why is this and what do you have to do to be able to identify isoforms with the same amount of repeats with the use of western blto?

Answer 15

You need to dephosphorylate the proteins first, otherwise the many phosphate group make it impossible to read the western blot.

Question 16

What is Pick’s disease?

Answer 16

A type of FTD → sporadic disease with tau inclusions.

Question 17

Mutations are found in a specific exon (exon 10?) that have been identified as the genetic cause of FTD. One of these mutations is a missense mutation P301L and causes FTD (FTLD-17 P301L). What can be found in brain slices when looked at histology?

Answer 17

Ballooned cells, a form of cell death where they increase in size.

Question 18

This picture displays a western blot of insoluble tau found in the frontal cortex. Explain what is seen.

Answer 18

Here, different suptypes of dementia are compared to each other. By dephosphorylating tau, the molecular weight of the isoforms of tau become visible. For example, in Alzheimer’s it’s seen that most isoforms have 3 or 4 repeats (3R/4R). While in suptypes of FTD (e.g. DDPAC) only isoforms with 4R are found. So there is a difference in the type of tau-inclusions that are found in the different subtypes.

Question 19

Just study the picture and see how different mutations in FTDP-17T (Frontotemporal Dementia and Parkinsonism linked to chromosome 17) can result in different morphology of tau inclusions.

Answer 19

Ok

Question 20

Also just study this picture, where different tau structures are depicted (due to different combinations of repeats).

Answer 20

Ok

Question 21

Fill in:

• Mutations in … and/or …, are mutations that (can) cause Alzheimer’s.
• Mutations in … are mutations that (can) cause Fronto-Temporal Dementia.

Answer 21

• Mutations in APP and/or PS are mutations that (can) cause Alzheimer’s.
• Mutations in Tau are mutations that (can) cause Fronto-Temporal Dementia.

Question 22

Wildtype mice and APP/PS1 mice don’t form tau tangles, while we need tangles for research about Alzheimer’s pathology in mice models. Mutations in APP/PS1 do result in formation of plaques.

What is needed to develop a mice model that contains plaques, but also tau tangles?

Answer 22

Using a triple transgenic mouse model for AD pathology. Besides introducing mutations for APP and PS1, also a tau mutation can be introduced. This way, a mice model can be developed that contains both plaques as tangles.

Question 23

What is the downside of developing a triple transgenic mouse model for AD pathology?

Answer 23

Because these mice now have 3 mutations (presenilin, APP and tau). The mutations in presenilin and APP lead to the formation of plaques, while the mutation in tau leads to tau tangles. This is not in line with the amyloid-beta cascade and makes this mice model not good for representing AD pathology.

Question 24

What happens when the expression of a mutant tau is induced in a mouse?

Answer 24

The mutant tau that will be expressed will aggregate and form tangles/inclusions. Formation of these inclusions leads to memory impairment.

Question 25

!!!!!! If it's possible to **activate** formation of tau tangles, it would also be possible to inactivate tau tangle formation. What happens if you switch off mutant tau expression?

Answer 25

!!!!!! Memory impairment is reduced, while the tangles remain.

Question 26

What is seen in this picture where neurons are stained with synaptophysin (staining for certain synaptic protein)?

Answer 26

That there's already loss of a synaptic protein at 3 months old, which indicates loss of synapses. At 3 months, mice haven't developed tau **tangles** yet (development of tangles starts at 6 months).

Question 27

What can be concluded based on this picture and the fact that tau tangles only develop from 6 months old mice?

Answer 27

That the smaller oligomers are more toxic than the fibrils/tangles. It's shown that inclusions don't need to be formed in order to develop a toxic phenotype.

Question 28

What is frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions?

Answer 28

It's a pathological process that occurs in FTD. It is characterized by atrophy in the frontal and temporal lobe of the brain. This type of pathology is usually characterized by the accumulation of tau proteins and TAR DNA-binding protein 43 (TDP-43).

Question 29

What other disease is characterized by frontotemporal lobarr degeneration with TDP-43 inclusions? And what's the difference between this disease and FTD?

Answer 29

FTLD with TDP-43 inclusions is also found in ALS. In ALS, the major inclusion is TDP-43. In FTD, also tau tangles are found.

Question 30

What is the (normal) function of TDP-43? What happens if TDP-43 is mutated?

Answer 30

It is a RNA binding protein and is important in RNA metabolism (i.e. splicing) and shuttles between the nucleus and cytoplasm. When mutated, TDP-43 sequesters in the cytoplasm. Here, TDP-43 is cleaved, ubiquitinated, reduced or hyperphosphorylated.

Question 31

What's seen in the picture?

Answer 31

That TDP-43 affects a lot of different RNA processes

Question 32

How does TDP-43 inclusions cause disease?

Answer 32

Normally TDP-43 shuttles between the nucleus and the cytoplasm and when mutated it mostly sequesters in the cytoplasm. So two things occur: * there's loss of normal function (since it can no longer act in the nucleus as a RNA-binding protein) * there's gain of toxic function (since it sequesters in the cytoplasm and interferes there with cellular processes) (But even this is uncertain, they don't fully know what happens with TDP-43 so that it causes disease)

Question 33

What is a common cause of FTD-ALS?

Answer 33

C9orf72 repeat expansion, this is a hexanucleotide repeat (G4C2) expansion in the non-coding (intronic) region of the C9orf72 gene.

Question 34

What other disease also is characterized by a repeat expansion? Also, what's the difference between this disease and ALS-FTD?

Answer 34

Huntington's disease, only the repeat expansion is in an exon instead of an intron.

Question 35

There are three different hypothesises for how C9orf72 repeat expansions cause FTD-ALS. Name these.

Answer 35

* Haploinsufficiency of C9orf72 gene, the intronic repeat expansion causes the gene to not be adequate to produce the needed gene product to preserve normal function (loss of function) * RNAs resulting from the C9orf72 intronic repeat expansion are though to form RNA foci that can bind to RNA binding proteins → repeat RNA-mediated toxicity (gain of toxic function) * The proteins that are formed by the C9orf72 intronic repeat expansion are called dipeptide protein repeats (DPRs) and can also aggregate (gain of toxic function).