Lecture 21 Flashcards
Accumulation f the AB peptide neurotoxicity is believed to be the ___likely initiating factor in synpatic/neuronal dysfunction and death
Accumulation f the AB peptide neurotoxicity is believed to be the most likely initiating factor in synpatic/neuronal dysfunction and death
True or false
The plaque forms of the AB peptide are the most dangerous version
Flase
oligomeric is the most damage inducing
Indirect oxidative stress can be induced by …
Interaction of amyloid with NMDA type glutamate receptor means too much calcuim gets into cells - death signals
Accumulation of intraneuronal AB can lead to …
Inhibition of cell metabolism - ep. protein turnover/axonal trafficking
Alters mitochondrial metabolism
Specifically, how is synaptic toxicity from AB induced?
NMDA receptor mediated
Impairment of vesicle release
INhibition of vesicle trafficking to synapse
Inhibition of endocytosis
general modulation of extracellular environment
Interactions of AB with receptors canc ause changes in intracelular cell signalling, what are some examples of these receptors?
NMDA glutamate receptor
Low density lipoprotein receptor
Acetylcholine receptor
Scavenger receptor
Fyn kinase receptor
ER stress (caused by build up of proteins) can signal to cell to slow down protein production, can lead to ______
apoptosis
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
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
Astrocytes protect neurons from ______ stress
oxidative stress
AB toxicity depends on tau interaction with ___ kinase in neuronal dendrites
fyn kinase
________ is possibly a major role in secondary neurotoxic effects in AD
Inflammation
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
__________
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
model systems, using _____ AB peptides are used to examine the neurotoxicity of the peptide
synthetic AB peptides
What are the problems with using synthetic Ab peptides for research?
Contamination with other toxic molecules
Normal brain also contains AB
Separation of different species
AB is very “sticky” and aggregates easily
Cell culture models can be neuroblastoma cell lines or ___ neuron cultures
Primary neuron cultures
True or False
Mixed glia/neuronal cultures are probably a better model of the brain
true
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)
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)
___ knockout is an example of how to study the effects of it on neurotoxicity
Fyn
If you mutate the histidine residues you affect __ binding and ______ neurotoxicity of peptide
If you mutate the histidine residues you affect Cu binding and reduce neurotoxicity of peptide
Mutation in Tyr19 also reduces _____
Mutation in Tyr19 also reduces toxicity
Optimal drugs for AD are:
Small Cross BBB non-toxic Cleared quickly - so you don't get accumulation Highly specific Easy to make in large quantities
______ mice can help study the APP gene
Transgenic mice can help study the APP gene
There are issues with over-expressing ______ compared to normal expression levels that occur in humans when looking at AD assays
There are issues with over-expressing proteins compared to normal expression levels that occur in humans
p301L tau mice can model the increased levels of hyperphosphorylated tau in the brain, formation of NFTs (Neurotrophic factors) but not necessarily have ______ deposits
p301L tau mice can model the increased levels of hyperphosphorylated tau in the brain, formation of NFTs but not necessarily have amyloid deposits
A number of crossed mice exist, what does this mean?
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
Studies support that changes to amyloid in AD are ______ of changes to tau (but the latter is critical for subsequent disease affects)
Studies support that changes to amyloid in AD are upstream of changes to tau (but the latter is critical for subsequent disease affects)
In reality, many proteins are _______ (as proteins do the same thing), so knocking out one has only subtle or no effect on the animal
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
APP-/- mice ______
APP-/- APLP2-/+ mice _____
APP-/- APLP2-/- mice ____________
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
other animals can be used as models:
Dogs
primates
zebra fish
fruit fly
