Lecture 24

Question 1

The beta and gamma secretases are responsible for …

Answer 1

formation of AB from APP - an obvious drug target

Question 2

Semagacestat, when given to patients, could lower…

Answer 2

Plasma, CSP and brain AB in animals and

lowered plasma and CSF AB in humans

Question 3

Phase III trials of Semagacestat showed that it…

Answer 3

doesn’t slow AD progression, but makes it worse (in measures of cognition)

Question 4

What are the problems with secretase inhibitors?

Answer 4

It’s non-selective,

gamma secretase doesn’t just cleave APP - cleaves other important proteins like NOTCH (can cause cancers)

Question 5

The active site of B-secretase is quite ____

Answer 5

large

Prominant trials at the moment

Question 6

_-______ can cleave APP to form non-neurotoxic species

Answer 6

alpha secretase

cleaves in middle of AB

Question 7

true or False

you can vaccinate against AB

Answer 7

true

Question 8

Immunised AD mouse model (APP transgenic) with the AB antigen shoed..

Answer 8

A reduction in amyloid plaques and AB levels

Question 9

Vaccination trials (AN 1792) for AD were problematic because?

Answer 9

No significant difference in mild-to-moderate patients

Trial was interrupted due to meningoencephalitis in 6% of patients (assoc. w T cell activation)

While there was a reduction in amyloid load, no evidence of improved survival

Question 10

Passive immunisation involved non-human (but humanised) antibodies being injected - which versions of AB does Bapineuzmab target?

how did it go?

Answer 10

soluble and fibrillar AB

bad results in phase I, II and II

Question 11

Solanezumab (monoclonal antibody, passive immunisation) preferentially targets which form of AB?

how did it go?

Answer 11

soluble AB (not as much)

no effect on behavioural outcomes

Question 12

True or False

Tau antibodies can reduce the number of NFTs in moderate and advanced stages only

Answer 12

False

All 3 groups showed reduction

before onset
moderate
advanced tau pathology

Question 13

Tramiprosate is a ….

what does it do?

how did it go?

Answer 13

oligomerisation inhibitor

Maintains AB in non-fibrillar form and reduce AB42-induced cell death

Failed in several clinical trials

Question 14

Clioquinol can ____ Zn and CU,

was found to…

Answer 14

chelates Zn and Cu

modulate amyloid pathology in APP transgenic mice

Question 15

PBT2 is a modified version of _______, shown to be able to work, but need to do the trial

Answer 15

Clioquinol

Question 16

Why have the major clinical trials failed?

Answer 16

they have targetted patients with mild to moderate disease state

need to target AB earlier

Question 17

PET machines can measure a modified form of thioflavin T (when binds to ______)

Answer 17

amyloid