Dementia

Question 1

Define the technique eImmunohistochemistry

Answer 1

this technique uses antibodies to visualise plaques in the ND brain.

Question 2

where are tau and AB plaques located

Answer 2

tau : inside the neuron

AB : outside the neuron

Question 3

what is the role of APP in Alzheimer’s

Answer 3

The beta and gamma secretase of this protein secretes AB oligomers.

Question 4

which two toxic AB oligomers are present in AD

Answer 4

AB-40 :

AB-42 : dangerous

Question 5

Define tau hyperphosphorylation

Answer 5

Tau binds to the microtubules in the cell and stabilises it. In ND’s tau can be phosphorylated which results in the release from these microtubules.

Hyperphosphorylation of tau leads to aggregation inside the neuron and destabilisation.

Question 6

what is the genetic evidence for causal role of AB oligomers

Answer 6

in Down syndrome there is evidence of AD pathology at 40-50 since there is an extra copy op APP producing chromosome.

this gives a higher risk to AD

Question 7

what is the most common cause of FAD (familial AD)

Answer 7

Mutations in presenilin (Presenilins (PSs) are the catalytic core of γ-secretase complex.)

• -> increases AB-42.
• -> directly involved in the formation of AB

Question 8

which protein is part of the gamma-secretase complex

Answer 8

PSEN1 in AD

Presenilin 1 deficiency inhibits Aβ formation

Question 9

AB oligomers inhibit LTP

Answer 9

aggregates AB bad ones

Question 10

what is a late-onset risk factor for AD

Answer 10

APOE, it is directly involved in the clearing of AB.

Question 11

what are the autosomal dominant forms of AD

what are the sporadic forms of AD

Answer 11

autosomal dominant forms of AD –> PSEN1, PSEN2, APP gene

sporadic forms of AD –> diet, age, head trauma, etc

Question 12

is there a positive mutation in the APP gene for AD?

Answer 12

Yes, there is a mutation which decreases the affect of gamma and beta secretase, preventing AB formation.

Arctic mutation in APP:

• Aβ decreased
• Increased formation of protofibrils

Question 13

is tau required for AB toxicity?

Answer 13

yes.

Question 14

Define the AB hypothesis cascade

Answer 14

1. overproduction/decreased clearance AB-42
2. AB-42 oligomerization
3. subtle effects of AB-42 on synapses
4. neuroinflammation
5. synaptic injury
6. altered neurohomeostasis
7. ROS production
8. cell death
9. dementia.

Question 15

what is FT(L)D

Answer 15

frontotemporal dementia

Question 16

what are the criteria of bvFTD (behavioral variant of Frontotemporal dementia (bvFTD))

Answer 16

1. disinhibited behaviour
2. apathy
3. loss of sympathy
4. compulsive behaviour

–> Memory is spared in FTD

Question 17

what is a specific feature of FTD

Answer 17

degeneration (atrophy) of the frontal lobe

Question 18

what are important inducers/mutations of FTD

what are important inducers/mutations of AD

Answer 18

AD:

1. APP
2. PSEN1

FLD:

1. TAU
2. TDP-43 (ALS)
3. C9ORF72 (ALS)

Question 19

what is the genetic cause of neurodegenration

Answer 19

genetic variants of FED are often associated with PD and MND (motto neuron diseases)

Question 20

how many isoforms of Tau are there, with how many binding domains

Answer 20

6, varying between 3-4 binding domains.

the isoforms with 3 binding domains bind less powerfully with microtubules.

Question 21

what is the cause of genetic FTD-tau forms

Answer 21

single amino acid missense mutation clustered on a specific axon.

Question 22

which tau isoforms are found in AD and in FLD?

Answer 22

AD: 3R-4R
FLD: only 4R

Question 23

which tau aggregate induced toxicity

Answer 23

the oligomeric precursor tau, these result in neuronal loss

Question 24

do you need tau inclusions to form a toxic phenotype

Answer 24

NO, the oligomers are more toxic than the fibrils (fibrils are inclusions).

Synapse loss (and microglial activation) precede tau inclusions

Question 25

what are inclusions

Answer 25

Inclusion bodies are aggregates of protein associated with many neurodegenerative diseases, accumulated in the cytoplasm or nucleus of neurons.

Question 26

what is the TDP-43 physiology

Answer 26

TDP-43 is a RNA binding protein. Normally it functions in normal RNA metabolism and it shuttles between the nucleus and the cytosol.

When mutated it locates more in the cytosol

Question 27

what is the role of C9ORF72 in TDP-43 mutations

Answer 27

C9ORF72 result in TDP-43 inclusions,

Question 28

what is a ballooned cell?

Answer 28

cell swelling and enlargement found particularly in steatohepatitis.