Lecture 23 - Therapeutics for Alzheimer's Disease

Question 1

Abeta load

Answer 1

Abeta synthesis - Abeta clearance

Question 2

Potential enzyme targets for AD therapy
1)
2)

Answer 2

1) Beta secretase

2) Gamma secretase

Question 3

Name of gamma secretase inhibitor

Answer 3

Semagacestat

Question 4

What is semagacestat?

Answer 4

A gamma secretase inhibitor

Question 5

What is gamma secretase?

Answer 5

A multi-subunit protein complex.
A protease.
Cleaves amyloid progenitor protein

Question 6

Effect of semagacestat
1)
2)

Answer 6

1) Dose-dependently lowers plasma, CSF and brain Abeta in animals, and lowered plasma and CDF Abeta in humans
2) In stage III clinical trail, did not slow Alzheimer’s.
Lead to worsening of measures of cognition

Question 7

Problem with gamma-secretase inhibitors

Answer 7

Many off-target effects, as they are quite non-selective

Question 8

Example of a non-gamma secretase target of semagacestat

Answer 8

NOTCH.

If NOTCH is cleaved, can lead to cancer development

Question 9

Beta-secretase inhibitor development
1)
2)

Answer 9

1) In early stages of development

2) Merck drug MK-8931 is undergoing stage 2 and 3 clinical trials

Question 10

Type of protease that beta secretase is

Answer 10

Aspartyl protease

Question 11

Another way to approach Alzheimer’s therapy by targeting proteases

Answer 11

Promote alpha secretase function.

Results in a truncated Abeta

Question 12

Basic idea of Alzheimer’s vaccine

Answer 12

Immunise with Abeta antigen

Question 13

Testing of Alzheimer’s vaccine idea

Answer 13

APP transgenic mice inoculated with Abeta vaccine

Question 14

Name of a putative Alzheimer’s vaccine

Answer 14

AN1792

Question 15

AN1792

Answer 15

Aggregated Abeta42 peptide antigen

Question 16

AN1792 trail outcome
1)
2)
3)

Answer 16

1) Stage II, mild to moderate AD patients immunised
2) No significant differences in cognitive tests between antibody responder and placebo groups
3) Had to stop trail because of 6% of patients developing meningoencephalitis

Question 17

AN1792 effects

Answer 17

Reduced number of Abeta plaques five years after immunisation, but this didn’t slow progression of neurodegeneration

6% rate of meningoencephalitis development

Question 18

Monoclonal antibody treatment for AD

Answer 18

Bapineuzumab

Humanised MAb against epitope Abeta1-5

Binds both soluble and fibrillar Abeta

Question 19

Bapineuzumab clinical trial results
1)
2)

Answer 19

1) Unpromising stage I and II

2) Failed in stage III trails. No difference between AD patients with or without ApoE4 allele

Question 20

ApoE4 gene

Answer 20

Greatest risk-factor gene for AD

Question 21

Why might it be dangerous to elicit an immune response against Abeta?

Answer 21

Abeta is a self protein.

Question 22

Attempted MAb therapies for AD

Answer 22

1) Bapineuzumab

2) Solanezumab

Question 23

Solanezumab

Answer 23

MAb therapy that binds to Abeta16-24

Preferentially binds to soluble Abeta

Question 24

Solanezumab clinical trial outcomes
1)
2)
3)

Answer 24

1) In AD mouse model, reversed memory effects without affecting Abeta load
2) Phase II trials, increased plasma and CSF levels of Abeta40 and 42, indicating that plaque load in brain was
decreased
3) In phase II and III trials, cognitive endpoints were not met

Question 25

MAb therapy that targets Abeta16-24

Answer 25

Solanezumab

Question 26

MAb therapy that targets Abeta1-5

Answer 26

Bapineuzumab

Question 27

AD vaccine targeting Tau

Answer 27

12aa sequence from human tau Comprised phosphorylated serine 396 and serine 404 epitope Reduced number of neurofibrillary tangles

Question 28

``` Tramiprosate 1) 2) 3) 4) ```

Answer 28

1) Oligomerisation inhibitor 2) Sulphated glycosaminoglycan mimetic 3) Maintains Abeta42 in non-fibrillar form 4) Reduces Abeta42-induced cell death

Question 29

Oligomerisation inhibition therapy

Answer 29

Tramiprosate

Question 30

Tramiprosate clinical trial outcomes

Answer 30

Failed to improve cognitive performance in definitive stage III trial

Question 31

What kind of drug is clioquinol?

Answer 31

Metal-protein attenuating compound

Question 32

Example of a metal-protein attenuating compound

Answer 32

Clioquinol

Question 33

Clioquinol mechanism of action

Answer 33

Chelates Cu and Zn This prevents Cu being able to form dityrosine crosslinks between Abeta monomers Crosses blood brain barrier Modulates amyloid pathology in transgenic mice

Question 34

Clioquinol clinical trial outcomes

Answer 34

Efficacious in a small-phase II human clinical trial

Question 35

Name of a modified version of Clioqunol

Answer 35

PBT2

Question 36

What is PBT2?

Answer 36

A modified version of Clioquinol

Question 37

Clinical trial outcome of PBT2

Answer 37

GFC hit when PBT2 was to go to trial, so only a small, underpowered trial could take place

Question 38

MCI

Answer 38

Mild cognitive impairment

Question 39

Peak age of AD onset

Answer 39

80

Question 40

When does prodromal AD (amnestic MCI) normally begin?

Answer 40

~10 years before onset of AD

Question 41

A way to test for AD 1) 2) 3)

Answer 41

1) Inject thioflavin T (radioactive marker) 2) PET scan patient 3) Thioflavin T relative fluorescence in area of brain with Abeta aggregation. This correlates with Braak staging of AD progression

Question 42

``` Possible AD treatments 1) 2) 3) 4) 5) ```

Answer 42

1) Secretase inhibitors 2) Vaccine (Abeta vaccine, tau vaccine) 3) Oligomerisation inhibitors 4) Metal-protein attenuating compounds 5) Antioxidants