4.15 BCHM - Biochem and Genetics of Dementia

Question 1

Identify the most prevalent form of dementia?

Answer 1

Alzheimer’s disease.

Question 2

Why is Alzheimer’s becoming more prevalent? What is the greatest risk factor for developing Alzheimer’s disease?

Answer 2

Alzheimer’s prevalence increases with age. We are getting older and older now due to modern technology.

Aging and genetics are the greatest risk factors for Alzheimer’s disease.

Question 3

What are 2 findings in pts with Alzheimer’s disease? What is the relationship between these findings and symptomatic findings in Alzheimer’s pts?

Answer 3

1st - amyloid-B plaques begin to accumulate 2 or 3 decades before symptoms appear.

2nd - neurofibrillary tangles begin to accumulate.

3rd - synaptic damage and neuronal death leads to atrophy especially in temporal lobes.

Lastly - symptoms appear: decreased cognitive impairment (cannot remember new information).

Question 4

What part of the brain is atrophy most prevalent in Alzheimer’s pts?

Answer 4

Neuronal cell death -> brain atrophy.

This is seen in the temporal lobe (hippocampus area) primarily.

Question 5

What are the 2 types of protein aggregates that are the hallmakrs of Alzheimer’s disease? (Where is each found, what are they made up of)?

Answer 5

Amyloid plaques: Extracellular, aggregates of amyloid-B (AB) = a ~40 amino acid long peptide cleaved from amyloid precursor protein (APP).

Neurofibrillary Tangles (NFTs): Intracellular, aggregates of hyperphosphorylated Tau protein.

Question 6

What is the Amyloid plaque hypothesis of Alzheimer’s diesease saying?

Answer 6

Plaques formed by amyloid-B protein, lead to inflammation, formation of tau neurofibrillary tangels, widespread neuronal cell death, and dementia ==> death.

Question 7

What is thought behind the amyloid-B oligomer hypothesis?

Answer 7

Amyloid-B also forms oligomers.

These oligomers can float around to different regions of the brain and cause neuronal damage and form plaques.

Some think plaques being formed are actually protecting from the oligomeric damage.

Question 8

What is the cross B structure of amyloid-B plaques? (how is it formed, describe its structure).

Answer 8

Amyloid-B fiber contains B-turn-B motif.

In this structure the backbone peptides hydrogen bond to adjacent identically folded peptide unit to form B-sheets.

These B-sheets are so long they form a fiber that is perpendicular to the peptide backbone of the individual B-strands or a “cross-B-structure”.

Question 9

There are two proteolytic pathways that amyloid precursor protein (APP) can take. What are these two proteolytic pathways? Which using which enzyme? Which is harmful, which is not?

Answer 9

Alpha-secretase pathway: initiated by proteolysis with alpha-secretase, harmless.

Beta-secretase pathway: initiated by proteolysis with B-secretase, harmful.

Question 10

What is the next step in the proteolytic pathway of APP? What structure results depending on the primary cleavage of APP?

Answer 10

APP next undergoes cleavage by y-secretase.

Alpha-secretase -> y-secretase => AICD, sAPPa, harmless p3.

Beta-secretase -> y-secretase => AICD. sAPPb, amyloid forming AB. AB42 + AB43 => plaque.

Question 11

How will the formation of AB peptides result in plaque?

Answer 11

AB-peptides folded into B-strand conformation -> aggregate into repetitive parallel B-sheet structures for entire length of B-amyloid fiber = cross-B-structures.

Question 12

Why are these proteases referred to as secretases?

Answer 12

They cleave proteins and these protein fragements are eventually released (secreted) outside the membrane.

Question 13

AB42, 43, 40 is made, which is most prevalent in plaques?

Answer 13

AB42, 42 amino acids long, hydrophobic and 90% of plaque is made from it.

Question 14

Which will lead to or decrease the incidence of Alzheimer’s:

a-secretase: inhibit or activate.

b-secretase: inhibit or activate.

y-secretase: inhibit or activate.

Answer 14

alpha-secretase: inhibition will allow the pathway to go down the AB plaque formation pathway = bad news. activation = good.

beta-secretase: inhibition = good (obvious reasons), activation = bad.

y-secretase: inhibition = good? stop AB from forming?, activation = bad?

Question 15

What is the difference between familial Alzheimer’s disease and sporatic Alzheimer’s disease? Which proteins are involved in these?

Answer 15

Familial Alzheimer’s disease: early onset. 1%. autsomal mutations in APP, Presinillin 1, Presinillin 2.

Sporadic Alzheimer’s disease: late onset. 99%. half is due to ApoEe4 polymorphism.

Question 16

In familial Alzheimer’s disease mutations in what three proteins cause what?

Answer 16

APP, presinillin 1 +2.

Affect processing of amyloid precursor protein (APP).

APP protein = direct structural mutation.

Presinillin 1 + 2 = y-secretase cleaving mutation.

Question 17

ApoE e4, e3, e2 are available polymorphisms. Which increases or decreases risk for Alzheimer’s?

Answer 17

ApoE e4 = increased.

ApoE e3 = neutral.

ApoE e2 = decreased.

Question 18

What is the function of apolipoprotein E in general? In the CNS?

Answer 18

Binds and carries lipids as lipoproteins from cells that make lipids to cells that need them.

In the CNS, astrocytes release cholesterol, ApoE binds LDL receptors and helps clear plaque (don’t know whats up).

Question 19

What are tauopathies? Which disease are these present in?

Answer 19

Dementias in which tau aggregates play a role.

A shit load of diseases (Alzheimer’s, Down’s syndrome, Pick’s, etc.).

Question 20

What is MAPT (stand for, function)?

Answer 20

Microtubule associated protein tau.

Assembles and stabilizes microtubules in axons.

Question 21

What happens when MAPT becomes hyperphosphorylated?

Answer 21

Becomes more soluble, does not bind microtubules, and won’t help build axons.

Question 22

What are the functions of healthy microtubules in axons?

Answer 22

Help move food, nutrients, etc. around, for excretion, etc.