Other Amyloid proteins

Question 1

There are two types of protein aggregates that can be generated- unordered aggregates and ordered aggregates - what are these called with other names?

Answer 1

Unordered aggregates = Amorphous

Ordered aggregates= fibrillar structure

Question 2

In what two groups can fibrillar structure aggregates be divided in?

Answer 2

• Amyloid fibrils

- non-amyloid fibrils

Question 3

Name the 5 criteria that a aggregate must fulfill to be classified as amyloid

Answer 3

1. The fibrils must have a width about 10 nm.
2. The fibrils must have a cross beta-sheet structure
3. Binding of congo red with a yellowgreen birefringence
4. Only extracellular not intracellular aggregates
5. Only in vivo formed, not fibrils formed in vitro (due to associated molecules)

Question 4

The following five criteria must classically be fulfilled for a protein to be classified as an amyloid - which of these are today questioned and why?1.The fibrils must have a width about 10 nm.

2. The fibrils must have a cross beta-sheet structure
3. Binding of congo red with a yellowgreen birefringence
4. Only extracellular not intracellular aggregates
5. Only in vivo formed, not fibrils formed in vitro (due to associated molecules)

Answer 4

Nr. 3, 4 and 5.

3. there are protein aggregates that fulfill other amyloid criteria but not this one, mainly in neurodegenerative diseases + there are other amyloid binding substances why should this one be the defining one?
4. Modern day research have found intracellular aggregates that fulfill other amyloid criterea, especially in neurodegenerative disorders
5. Research that are conducted today with amyloid proteins are done in vitro.

Question 5

What is the term of a disease caused by amyloid deposits?

Answer 5

Amyloidosis

Question 6

What is a systemic amyloidosis and what is its characteristics?

Answer 6

It is a amyloidosis in which the fibril protein is a plasma protein. This will result in deposits in basically every organ (besides CNS). The deposition is not compleatly homogenous though, it can accumulate more in certain organs. It is characterized by large amounts of amyloid (kg) which always lead to disease and always is deadly if not treated. Always extracellular.

Question 7

Why is aggregation harmful in local amyloidosis and systemic amyloidosis respectively?

Answer 7

Local: loss of (normal) function + gain of (toxic) function (toxic oligomers)
Systemic: loss of (normal) function + gain of (toxic) function (toxic oligomers) + mass effect - physical hindrance, destroys the organs architecture

Question 8

There is a discussion about if several local amyloidosis really should be classified as amyloidosis, how come?

Answer 8

It is often not clear if the amyloid deposits is the cause (definition of amyloidosis) or a consequence of the disease

Question 9

Which protein is amyloidogenic and are found in the pancreas of 90% of diabetes mellitus type 2 patients?

Answer 9

IAPP- islet amyloid polypeptide

Question 10

Does the IAPP amyloid formation in diabetes mellitus type 2 contribute to the pathogenesis?

Answer 10

It is now recognized as a contributing factor to the pathogenesis but it is unclear how much it contributes

Question 11

Give at least 3 examples of ways AD are connected with Diabetes Mellitus type 2

Answer 11

• AD associated with insulin resistance
• Glucose dysregulation affecting the brain
• IAPP are found in the A-beta deposits
• IAPP amyloid found in AD brains
• expressing human IAPP in AD mice caused increased pathology
• IAPP can trigger A-beta amyloid formation in vitro

Question 12

Medin is an example of a protein which can cause local amyloidosis, where does it usually aggregate?

Answer 12

Medin amyloid are localized in the wall of the aorta

Question 13

In systemic amyloidosis, does the aggregates form in the circulating blood or once they reach the tissue?

Answer 13

It is still unclear

Question 14

How do you name a systemic amyloid fibril protein?

Answer 14

“A” + “short for the precursor protein” (eg. TTR for transthyretin)

Question 15

Which three are the most common systemic amyloidosis?

Answer 15

AA, AL and ATTR

Question 16

AA, AL and ATTR are examples of systematic amyloidosis, what protein are affected in respective disease?

Answer 16

AA- serum amyloid A (an apolipoprotein/acute phase protein)
AL- Immunoglobulin light chain
ATTR- Transthyretin

Question 17

Why was AA amyloidosis previously called secondary amyloidosis?

Answer 17

Because it is usually a complication (secondary to) of chronic inflammation such as RA, Chron’s disease etc.

Question 18

What organ is especially affected by AA amyloidosis?

Answer 18

The kidney, kidney insufficiency is usually the cause of death

Question 19

What’s the treatment of AA amyloidosis?

Answer 19

• drugs aimed at inhibit aggregation- under development
• reducing the concentration of Serum amyloid A in the circulation by treatment of the chronic inflammation - cortical steroids and cytostatic drugs

Question 20

Compared to other systemic amyloidois, what is special about AA

Answer 20

AA amyloid dissolves more easily than other systemic amyloid deposits

Question 21

What is the cause of amyloid deposits in AL amyloidosis?

Answer 21

A clonal expansion of plasma cells (activated B-cells) which therefore produce excess a light chain protein

Question 22

Why is the deposition pattern/clinical symptoms of AL amyloidosis so variable?

Answer 22

It is due to that the amino acid sequence of the light chain varies

Question 23

Give examples of where the AL amyloid deposits can accumulate?

Answer 23

Heart, liver, kidney, nerves, skin, tung etc.

Question 24

How long does a patient with AL amyloidosis usually survive after diagnosis?

Answer 24

About 1 year but only 6 months if the patient has cardiac amyloid

Question 25

What’s the treatment of AL amyloidosis?

Answer 25

-Drugs aimed at inhibit aggregation is under development
-Instead try to reduce the amount of light chains in the circulation, i.e.
Attack the plasma cell clone, similar to myeloma treatment
-Cytostatic drugs or stem cell transplantation

Question 26

ATTR can be both spontaneous and hereditary, what’s the pattern of inheritance?

Answer 26

Autosomal dominant
(several mutations - same pattern of inheritance)

Question 27

What organs are affected in ATTR?

Answer 27

It varies between patient to patient both between the TTR mutations and between patients with the same TTR mutation. But for example peripheral nerves, heart, kidney, eyes and CNS

Question 28

How long does a patient with ATTR amyloidosis usually survive without treatment?

Answer 28

10-15 years

Question 29

What’s the treatment of ATTR (hereditary) amyloidosis?

Answer 29

• liver transplantation
• tetramer stabalizers (it’s the monomeric form that aggregates)
• RNA interference (RNAi) which reduce the TTR concentration in the blood (first RNAi drug to be approved)

Question 30

Is there a different in clinical apearence of spontaneous amyloidosis and hereditary?

Answer 30

Yes, the spontanous affects the elderly usually above 70 yrs and are found in 25% of induviduals above 80. It is often asymptomatic and the amyloid deposits are usually found in the heart but also in ligaments, blood vessels, lungs, nerves etc.

Question 31

What’s the treatment of ATTR (spontanous) amyloidosis?

Answer 31

• Tetramer stabilizer recently approved for wtATTR
  amyloidosis
• RNAi drugs not approved yet