A-beta and Tau

Question 1

GFAP is a marker for…

Answer 1

Astrocytes

Question 2

CD11b is a marker for…

Answer 2

Microglia

Question 3

What is the pathological characteristics of Alzheimers disease?

Answer 3

Amyloid-beta plaques (senile plaques) and tau tangles (neurofibrillary tangles)

Question 4

What is the pathological characteristics of Frontotemporal dementia?

Answer 4

Tau pick bodies and TDP-43 incusions

Question 5

What is the pathological characteristics of Parkinsons disease and Lewy body dementia?

Answer 5

Lewy bodies and Lewy neurites consiting of alpha-synuclein

Question 6

Which macroscopical characteristics has an AD brain?

Answer 6

Smaller, larger ventricles and widened sulci = cerebral atrophy

Question 7

Are the senile plaques (A-beta plaques) intracellular or extracellular?

Answer 7

Extracellular

Question 8

Are the neurofibrillary (tau) tangles intracellular or extracellular?

Answer 8

Intracellular

Question 9

Name at least one content of senile plaques which is not amyloid beta.

Answer 9

1. heparan sufate
2. glycolipids
3. ApoE
   etc

Question 10

Is alpha secretase an enzyme in the amyloidogenic pathway or the non-amyloidgenic pathway?

Answer 10

non-amyloidogenic pathway

Question 11

Is beta secretase an enzyme in the amyloidogenic pathway or the non-amyloidgenic pathway?

Answer 11

amyloidogenic pathway

Question 12

Is gamma secretase an enzyme in the amyloidogenic pathway or the non-amyloidgenic pathway?

Answer 12

amyloidogenic pathway

Question 13

Mutations in Presenilin 1 and 2 are genes which causes famillial AD. How is these proteins involved in the Amyloid beta precursor protein processing?

Answer 13

They are two of the four subunits of the gamma secretase

Question 14

How many amino acids does the type of amyloid beta have which is most prone to aggregation

Answer 14

42 (A-beta 42)

Question 15

Name one physiological function Amyloid beta may have

Answer 15

synaptic function

antimicrobial function

Question 16

Which of the following forms of amyloid beta aggregates are insoluble:

• dimers
• tetramers
• protofibrils
• prefibrillar oligomers
• ADDLS gobulomers amylospheroids
• fibrils

Answer 16

Fibrils

Question 17

The so called Swedish mutation is a mutation which causes a famillial type of AD, which protein is mutated, where in the protein sequence and what is the result of the mutation?

Answer 17

It is a mutation in the gene for the APP (amyloid precursor protein) close to the cleavage site of beta secretase. It is outside of the amyloid beta sequence but will affect the beta secretase cleavage and cause an increased Amyloid beta concentration

Question 18

The so called London mutation is a mutation which causes a famillial type of AD, which protein is mutated, where in the protein sequence and what is the result of the mutation?

Answer 18

It is a mutation in the gene for the APP (amyloid precursor protein) close to the cleavage site of gamma secretase. It is outside of the amyloid beta sequence but will affect the gamma secretase cleavage, this will result in an increased concentration of amyloid beta 42, which is a variant of A-beta which is more prone to agregate

Question 19

The so called Arctic mutation is a mutation which causes a famillial type of AD, which protein is mutated, where in the protein sequence and what is the result of the mutation?

Answer 19

It is a mutation in the gene for the APP (amyloid precursor protein). It is located in the middle of the amyloid beta sequense and will affect the amyloid betas propensity to aggregate

Question 20

Which forms of amyloid beta is thought to be most neurotoxic

Answer 20

the Amyloid beta oligomers and protofibrils (the soluble aggregates)

Question 21

What is the consequense of a mutation in the presenilin 1/ 2?

Answer 21

Increased Amyloid beta 42/40 ratio (causes familial AD)

Question 22

Amyloid beta oligomers have been proposed to interact with several postsynaptic receptors, what is the consequence of this?

Answer 22

It will lead to synaptotoxicity and neuronal loss

e.g. loss of dendritic spines

Question 23

In the disease progression of AD, which pathology is seen first tau or amyloid beta?

Answer 23

amyloid beta (tau is secondary to amyloid beta)

Question 24

In AD is amyloid beta pathology or tau pathology best correlated with the clinical disease progression and the neuronal loss of integrity?

Answer 24

Tau

Question 25

Where does the neuronal loss start in AD and how does it spread from there?

Answer 25

It starts in the hippocampus and spreads via the temporal and parietal lobes to the frontal lobe

Question 26

What is tau’s physiological function?

Answer 26

It is involved in the formation and stabilization of microtubuli

Question 27

Which form of monomeric tau are most prone to aggregate?

Answer 27

The phosphorylated tau

Question 28

Name one consequence of tau aggregation?

Answer 28

It will cause the microtubuli to disintegrate, dysfuction in the axonal transport and the tau aggregates are neurotoxic

Question 29

What is the consequence of a mutation in the gene sequence of tau?

Answer 29

it will lead to the formation of neurofibrillary tangles and cause a disease called frontotemporal dementia

Question 30

Name three mechanisms in which a mutation in the tau gene can cause frontotemporal dementia.

Answer 30

1. It will cause tau to bind less to the microtubuli
2. it will increase the aggreagation of tau
3. it will increase the formation of tau with four microtubule binding domains which will cause imbalance between tau isoforms in the cell, which increases the aggregation

Question 31

In AD the levels of amyloid beta in CSF will…

Answer 31

Decrease (due to accumulation in the plaques)

Question 32

In AD the levels of tau (total tau) in CSF will…

Answer 32

increase (due to general neurodegeneration)

Question 33

In AD the levels of p-tau in CSF will…

Answer 33

increase (due to increase of NFT formation)