Lecture 21

Question 1

Accumulation f the AB peptide neurotoxicity is believed to be the ___likely initiating factor in synpatic/neuronal dysfunction and death

Answer 1

Accumulation f the AB peptide neurotoxicity is believed to be the most likely initiating factor in synpatic/neuronal dysfunction and death

Question 2

True or false

The plaque forms of the AB peptide are the most dangerous version

Answer 2

Flase

oligomeric is the most damage inducing

Question 3

Indirect oxidative stress can be induced by …

Answer 3

Interaction of amyloid with NMDA type glutamate receptor means too much calcuim gets into cells - death signals

Question 4

Accumulation of intraneuronal AB can lead to …

Answer 4

Inhibition of cell metabolism - ep. protein turnover/axonal trafficking

Alters mitochondrial metabolism

Question 5

Specifically, how is synaptic toxicity from AB induced?

Answer 5

NMDA receptor mediated

Impairment of vesicle release

INhibition of vesicle trafficking to synapse

Inhibition of endocytosis

general modulation of extracellular environment

Question 6

Interactions of AB with receptors canc ause changes in intracelular cell signalling, what are some examples of these receptors?

Answer 6

NMDA glutamate receptor

Low density lipoprotein receptor

Acetylcholine receptor

Scavenger receptor

Fyn kinase receptor

Question 7

ER stress (caused by build up of proteins) can signal to cell to slow down protein production, can lead to ______

Answer 7

apoptosis

Question 8

Astroctye regulate extracellular ______ levels. (Among other things)

too much ________ can get overestimation and activation of cell death pathways

Astrocyte take up the excess _____ through _______ receptors

Answer 8

Astroctye regulate extracellular glutamate levels.

too much glutamate can get overestimation and activation of cell death pathways

Astrocyte take up the exccess glutatame through glutamate receptors

Question 9

Astrocytes protect neurons from ______ stress

Answer 9

oxidative stress

Question 10

AB toxicity depends on tau interaction with ___ kinase in neuronal dendrites

Answer 10

fyn kinase

Question 11

________ is possibly a major role in secondary neurotoxic effects in AD

Answer 11

Inflammation

Question 12

A summary of the neurotocix effects of amyloid peptide (oligomeric):

generation of ___

indirect increase in oxidative stress through _____ _______

__________ cell signaling

Impaired _______ transport

___ stress

Inhibition of _______ uptake by astrocytes

_________ energy levels

________ trophic support

__________

Answer 12

generation of ROS

indirect increase in oxidative tress through NMDA glutamate

Abberant cell signaling

Impaired axonal transport

ER stress

Inhibition of glutamate uptake by astrocytes

Decreased energy levels

Decreased trophic support

Inflammation

Question 13

model systems, using _____ AB peptides are used to examine the neurotoxicity of the peptide

Answer 13

synthetic AB peptides

Question 14

What are the problems with using synthetic Ab peptides for research?

Answer 14

Contamination with other toxic molecules

Normal brain also contains AB

Separation of different species

AB is very “sticky” and aggregates easily

Question 15

Cell culture models can be neuroblastoma cell lines or ___ neuron cultures

Answer 15

Primary neuron cultures

Question 16

True or False

Mixed glia/neuronal cultures are probably a better model of the brain

Answer 16

true

Question 17

The MMT/MTS assay is good for measuring subtle changes in cell ______ (and is rapid and simple)

But is disadvantaged in that it:

doesn’t tell if cells are just unhealthy or ___

If cells aren’t _______ this will increase the measured viablilty in spite of death of other cells

Assay compunds are __ to cells

Not ___-time (end-point assay only)

Answer 17

The MMT assay is good for measuring subtle changes in cell toxicity (and is rapid and simple)

but is disadvantaged in that it:

doesn’t tell if cells are just unhealthy or dead - both have the same readout

If cells aren’t replicating this will increase the measured viablilty in spite of death of other cells

Assay compounds are toxic to cells

Not real-time (end-point assay only)

Question 18

___ knockout is an example of how to study the effects of it on neurotoxicity

Answer 18

Fyn

Question 19

If you mutate the histidine residues you affect __ binding and ______ neurotoxicity of peptide

Answer 19

If you mutate the histidine residues you affect Cu binding and reduce neurotoxicity of peptide

Question 20

Mutation in Tyr19 also reduces _____

Answer 20

Mutation in Tyr19 also reduces toxicity

Question 21

Optimal drugs for AD are:

Answer 21

Small
Cross BBB
non-toxic
Cleared quickly - so you don't get accumulation
Highly specific
Easy to make in large quantities

Question 22

______ mice can help study the APP gene

Answer 22

Transgenic mice can help study the APP gene

Question 23

There are issues with over-expressing ______ compared to normal expression levels that occur in humans when looking at AD assays

Answer 23

There are issues with over-expressing proteins compared to normal expression levels that occur in humans

Question 24

p301L tau mice can model the increased levels of hyperphosphorylated tau in the brain, formation of NFTs (Neurotrophic factors) but not necessarily have ______ deposits

Answer 24

p301L tau mice can model the increased levels of hyperphosphorylated tau in the brain, formation of NFTs but not necessarily have amyloid deposits

Question 25

A number of crossed mice exist, what does this mean?

Answer 25

cross breeding APP mutant mice with Tau mutant mice

• induces increased levels are more rapid onset of neuropathological features, but rarely anything different to amyloid mice

Question 26

Studies support that changes to amyloid in AD are ______ of changes to tau (but the latter is critical for subsequent disease affects)

Answer 26

Studies support that changes to amyloid in AD are upstream of changes to tau (but the latter is critical for subsequent disease affects)

Question 27

In reality, many proteins are _______ (as proteins do the same thing), so knocking out one has only subtle or no effect on the animal

Answer 27

In reality, many proteins are redundant (as proteins do the same thing), so knocking out one has only subtle or no effect on the animal

Question 28

APP-/- mice ______
APP-/- APLP2-/+ mice _____
APP-/- APLP2-/- mice ____________

Answer 28

APP-/- mice Survive
APP-/- APLP2-/+ mice survive
APP-/- APLP2-/- mice die at embryonic stage

so even one copy of APLP2 can cover for APP in normal brain function

Question 29

other animals can be used as models:

Answer 29

Dogs
primates
zebra fish
fruit fly