Lecture neurodegenerative disorders 2: Alzheimer's disease

Question 1

What are symptoms of Alzheimer’s disease?

Answer 1

• Loss of memory
• Loss of orientation in time and space
• Language difficulties
• Behavioural changes
• Personality changes

Question 2

Describe the pathology of Alzheimer’s disease.

Answer 2

Accumulation of extracellular amyloid-beta and intracellular accumulation of tau-tangles.

Question 3

What is the amyloid cascade hypothesis?

Answer 3

It states that amyloid-beta (AB) is the most important player that causes cognitive dysfunction.

Here, accumulation of AB leads to oligomerization of AB and formation of diffuse plaques. AB oligomers affect synapses, which causes microglia and astrocyte acitvation that damages synapses and neurites even more. This causes alteration in neuronal ionic homeostasis, which disrupts the function of tau, hyperphosphorylating tau and creating tau-tangles. These tau-tangles cause neuronal/neuritic dysfunction and cell death. This ultimately leads to dementia.

Question 4

Describe how amyloid beta plaques are synthesized.

Answer 4

Amyloid Precursor Protein (APP) is normally cut by α-secretase, where non-amyloidogenic amyloid protein is produced as a consequence. But if APP is cleaved by β- en γ-secretase, amyloidogenic amyloid is produced that is either 40 or 42 amino acids long.

Question 5

Where does amyloid-beta accumulate and which of the two subtypes is more prone to aggregate?

Answer 5

Amyloid-beta accumulates outside of the cell, where the 42 amino acid long amyloid-beta is more prone to aggregation.

Question 6

What kind of protein is Tau?

Answer 6

Tau is a microtubule binding protein that stabilises microtubules. For transport across microtubuli, it’s important that tau is able to detach itself from the microtubules. This is done by phosphorylation of tau.

Question 7

How are tau-tangles/aggregates formed?

Answer 7

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 8

Name two things that provide genetic evidence for the causal role of amyloid-beta?

Answer 8

• People with Down syndrome develop Alzheimer’s disease around their 40s/50s. There 21th chromosome is duplicated (trisomy), this chromosome also contains the APP-gene.
• Families with Early-Onset Alzheimer’s Disease (EOAD) and Cerebral Amyloid Angiopathy (CAA) have been identified with APP duplications.

Question 9

Describe characterization of Familial Alzheimer’s Disease (FAD)

Answer 9

• Early onset
• Autosomal dominant

Question 10

What do mutations in the APP gene in familial AD lead to?

Answer 10

• Increase in AB levels
• Increase ratio of AB(1-42)/AB(1-40)

Question 11

What kind of advantage is there for the fact that genetic variants exist in familial AD?

Answer 11

That this can be modelled in cells or mice for research

Question 12

What mutation is the most common cause of familial AD?

Answer 12

Mutations in the Presenilin gene (PSEN1/PSEN2). As you can also see in this picture, you can see that a mutation in Presenilin enhances AB pathology compared to only mutated APP.

Question 13

How can the function of Presenilin 1 be researched?

Answer 13

By making a PSEN1 knock-out mouse.

Question 14

So to research the function of PSEN1, a knock-out mouse is generated. It appears that a knock-out of PSEN1 is lethal to the mouse. What is the next step to investigate its function?

Answer 14

By obtaining embryos before birth and culturing the neurons in vitro.

Question 15

By crossing heterozygous mice, you can create knock-out mice without PSEN1 (-/-) and knock-in mice with PSEN1 (+/+). How much AB is produced in both mice?

Answer 15

PSEN1 deficient mice (-/-) produce less AB compared to mice containing PSEN1 (+/+). So PSEN1 deficiency inhibits AB formation.

Question 16

Why does mutated PSEN1 with mutated APP enhance AB pathology?

Answer 16

PSEN1 is the catalytic part of γ-secretase and so is directly involved in the production of AB. So when PSEN is mutated, it has direct consequences on AB formation.

Question 17

Just study

Answer 17

Ok

Question 18

Fill in:

It has already been stated that AB … (aggregation state of AB) are presumed to be the most toxic. Therefore, these AB plaques are able to inhibit/prevent …

Answer 18

It has already been stated that AB oligomers are presumed to be the most toxic. Therefore, these AB plaques are able to inhibit/prevent Long-Term Potentiation (LTP).

Question 19

What is Long-Term Potentiation?

Answer 19

A long-lasting strengthening of the response of a postsynaptic nerve cell to stimulation across the synapse that occurs with repeated stimulation. It is important in learning and long-term memory.

Question 20

What is the arctic APP-mutation?

Answer 20

A point mutation of the APP gene found in residents from Lapland. This mutations causes an increase in the production of protofibrils, which causes strong aggregation of AB. (It also proves why oligomers are the most toxic)

Question 21

Fill in:

1. A mutation in APP leads to a molecular phenotype with: ….
2. A mutation in PSEN1 leads to a molecular phenotype with: ….
3. A mutation in PSEN2 leads to a molecular phenotype with: ….

Answer 21

1. A mutation in APP leads to a molecular phenotype with: increased AB(42)/AB(40) ratio, AB production and aggregation.
2. A mutation in PSEN1 leads to a molecular phenotype with: increased AB(42)/AB(40) ratio
3. A mutation in PSEN2 leads to a molecular phenotype with: increased AB(42)/AB(40) ratio

Question 22

What gene is associated with late-onset AD?

Answer 22

The APOE gene encoding for a protein called apolipoprotein E, important in clearance of AB and lipid metabolism.

Question 23

You can look for risk factors that increase the risk for AD, but you can also look for factors that work protective against AD. This has actually been done in an Icelandic cohort in people over 85 with AD or without AD. What did they found?

Answer 23

They found an APP mutation (A673T) that gives a 5x higher chance to reach 85 without developing AD. This mutation reduces BACE1 cleavage of APP and with this producing less AB.

Question 24

Name characteristics of autosomal dominant AD

Answer 24

• Age of onset between 30 and 60 years
• Mutations in: APP, PSEN1 and PSEN2

Question 25

Name characteristics of sporadic AD

Answer 25

• Age of onset +/- 65 years
• Increased risk with APOE E4 isoform
• Risk factors like age, dietary, head trauma etc.

Question 26

APP mice with amyloid-β plaques do not develop tau tangles and show limited loss of neurons. What could this say?

Answer 26

That tau might be required for AB toxicity

Question 27

How did they test whether tau is required for AB toxicity and what was the result?

Answer 27

By generating mice that expressed only tau, both APP as tau or none of the two. They tested these mice in a watermaze for memory and survival. They saw that only when tau and APP was present, mice lost their memory and survival.

Question 28

Why is there a need for early diagnosis of AD?

Answer 28

Because a lot of processes in the brain are changed already when the first AD symptom sets on, as can be seen in the picture.