Lecture 23 - Therapeutics for Alzheimer's Disease Flashcards Preview

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Flashcards in Lecture 23 - Therapeutics for Alzheimer's Disease Deck (42):
1

Abeta load

Abeta synthesis - Abeta clearance

2

Potential enzyme targets for AD therapy
1)
2)

1) Beta secretase
2) Gamma secretase

3

Name of gamma secretase inhibitor

Semagacestat

4

What is semagacestat?

A gamma secretase inhibitor

5

What is gamma secretase?

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

6

Effect of semagacestat
1)
2)

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

7

Problem with gamma-secretase inhibitors

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

8

Example of a non-gamma secretase target of semagacestat

NOTCH.
If NOTCH is cleaved, can lead to cancer development

9

Beta-secretase inhibitor development
1)
2)

1) In early stages of development
2) Merck drug MK-8931 is undergoing stage 2 and 3 clinical trials

10

Type of protease that beta secretase is

Aspartyl protease

11

Another way to approach Alzheimer's therapy by targeting proteases

Promote alpha secretase function.
Results in a truncated Abeta

12

Basic idea of Alzheimer's vaccine

Immunise with Abeta antigen

13

Testing of Alzheimer's vaccine idea

APP transgenic mice inoculated with Abeta vaccine

14

Name of a putative Alzheimer's vaccine

AN1792

15

AN1792

Aggregated Abeta42 peptide antigen

16

AN1792 trail outcome
1)
2)
3)

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

17

AN1792 effects

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

6% rate of meningoencephalitis development

18

Monoclonal antibody treatment for AD

Bapineuzumab

Humanised MAb against epitope Abeta1-5

Binds both soluble and fibrillar Abeta

19

Bapineuzumab clinical trial results
1)
2)

1) Unpromising stage I and II
2) Failed in stage III trails. No difference between AD patients with or without ApoE4 allele

20

ApoE4 gene

Greatest risk-factor gene for AD

21

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

Abeta is a self protein.

22

Attempted MAb therapies for AD

1) Bapineuzumab
2) Solanezumab

23

Solanezumab

MAb therapy that binds to Abeta16-24

Preferentially binds to soluble Abeta

24

Solanezumab clinical trial outcomes
1)
2)
3)

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

25

MAb therapy that targets Abeta16-24

Solanezumab

26

MAb therapy that targets Abeta1-5

Bapineuzumab

27

AD vaccine targeting Tau

12aa sequence from human tau
Comprised phosphorylated serine 396 and serine 404 epitope

Reduced number of neurofibrillary tangles

28

Tramiprosate
1)
2)
3)
4)

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

29

Oligomerisation inhibition therapy

Tramiprosate

30

Tramiprosate clinical trial outcomes

Failed to improve cognitive performance in definitive stage III trial

31

What kind of drug is clioquinol?

Metal-protein attenuating compound

32

Example of a metal-protein attenuating compound

Clioquinol

33

Clioquinol mechanism of action

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

34

Clioquinol clinical trial outcomes

Efficacious in a small-phase II human clinical trial

35

Name of a modified version of Clioqunol

PBT2

36

What is PBT2?

A modified version of Clioquinol

37

Clinical trial outcome of PBT2

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

38

MCI

Mild cognitive impairment

39

Peak age of AD onset

80

40

When does prodromal AD (amnestic MCI) normally begin?

~10 years before onset of AD

41

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

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

42

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

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