therapy studies

Question 1

stimulation of cholinergic transmission in AD

Answer 1

theme

Question 2

what are registered treatments for AD

Answer 2

1. acetylcholinesterase inhibitors (AD had acetylcholine shortage)
2. NMDA receptor blockers (prevents glutamate overstimulation)
3. gamma-secretase inhibitors

Question 3

which treatment is registered for PD

Answer 3

L-dopa, but it has many side effects (dopamine extra)

stem cell transplantation

Question 4

what are NSAID’s

Answer 4

non-steroid anti-inflammatory drugs

with NSAID’s you inhabit the production of ROS by inhibiting COX1 and COX2

Question 5

THERAPY 2

Question 6

describe the four phases of clinical trials

Answer 6

1. research in safety and maximum dosage
2. efficacy and selective dosing
3. larger research group
4. post marketing

Question 7

describe CSF (Cerebrospinal fluid) diagnosis in AD

Answer 7

AB is decreased in the Cerebrospinal fluid

tau is increased in Cerebrospinal fluid

Question 8

descrive CSF diagnosis in CJD (prion)

Answer 8

14-3-3 biomarker for CJB found in Cerebrospinal fluid

Question 9

what other target do gamma-inhibitors have

Answer 9

Notch signalling (found in cancer)

Question 10

BACE inhibitors worsen cognition

Answer 10

APP is not a good substrate for BACE ( b-secretase inhibitors)

Question 11

is immune therapy a possible treatment for AD

Answer 11

antibodies can reduce the amount of AB according to the hypothesis:

1. antibodies cross the BBB and bind to AB
2. AB crosses the BBB and binds to antibodies in the bloodstream.

Question 12

active immunisation of APP in mice revealed…

Answer 12

transgenic APP mouse with plaques are treated with antibodies and resulted in memory repairment.

Question 13

what happend with the synaptophysin reactivity after AB vaccination

Answer 13

synaptophysin reactivity increased, but with severe side effects.

vaccination example: Solanezumab (vaccine against AB-42), PE3 (vaccine against PyroGlu)

Question 14

which influence does pyroglutamate have over AB

Answer 14

it modifies AB to aggregate faster (it modifies the N-term. from Glu to PyroGlu)
it also decreases the viability drastically of Neurons

The modification of AB is done by the enzyme glutaminyl cyclase (QC)

Question 15

does the inhibition of QC have effect on AB plaques

Answer 15

PBD150 inhibits QC.

it shows prevention of plaque formation, but no reduction of plaques

Question 16

THERAPY 3

Question 17

which proteins mediate UPR

Answer 17

PERK, IRE1, ATF6

Question 18

how can you monitor UPR

Answer 18

via phosphorylation, splicing, transcription and translocation

Question 19

with which pathology is UPR associated

Answer 19

tau pathology, in AD (UPR is an early tau event)

Question 20

what does the activation of PERK induce

Answer 20

the inhibition of translation in protein synthesis

Question 21

Define the cascade induces after UPR activation

Answer 21

1. prions
2. activated UPR
3. Activation PERK
4. reduction protein synthesis
5. depletion SNAP25 and PSD95
6. neurodegeneration

Question 22

what is the consequence of inhibition of elFaP (PERK pathway look-alike)

Answer 22

rescues synaptic failure and neurodegeneration, and restores synaptic protein levels.

Question 23

name the PERK cascade

Answer 23

PERK –> P-elF2a –> elF2a

Question 24

what is the consequence of PERK inhibition

Answer 24

diabetes

it does rescue protein synthesis and interferes with tau-pathology

Question 25

what kind of inhibitor is ISRIB

Answer 25

elF2A inhibitor, targeting more downstream targets of PERK pathway.

Question 26

what are the effects of ISRIB

Answer 26

reduction of neurodegeneration in prion mice.

Question 27

which drugs inhibit dephosphorylation of P-elF2a

Answer 27

Salubrinal : inhibits all dephosphorylation | Guanaben: only inhibits stress induced dephosphorylation (creates hypertension)

Question 28

does the dephosphorylation of P-elF2a work

Answer 28

NO, opposite effect