Download Backup of Karen duff

Karen duff
In app there are two main mutations and they cause the cutting of the app molecule that
will lead it to go more along the path that leads to amyloid plaques
Other mutations were found in other genes, like PS, it increases the cutting at one of the
sites in app. While it’s not an app mutation, it affects that pathway. It’s likely that other
genes also affect that pathway.
There are many genes implicated and some have stronger implication than others. And
some come and go. The big findings were in the early 1990s and since then it has slowed
down. But the pathway seems to be the same in all these patients.
When you look at an Alz brain you see two lesions: plaques and neurofib tangles and you
have to have those two features to have AD, but that might just be a pathologists
definition. It’s not based on mechanism or genetics, it’s based on what Alz saw in 1906.
the impact of the tangls may be very significant. That’s only just now beginning to be
worked out. The reason the tau was thought of less is because there were no mutations
in the gene that is involved in tangle formation until very recently, and those mutations
don’t cause Alz, they cause other diseases.
The amyloid story has waxed and waned. It was really the predominant story five years
ago after they found the mutations in app and PS, it was converging on the same pathway
it really focused people on this being the important target. The drug companies like it,
it’s extracellular.
It’s fairly easy to target
There are subtlies in the amy story. What you see in the brain is an amy plaque, but
what’s happening in the brain might be happening way before the amyloid plaque
And there’s even some ideas that the amyloid plaque is protective because it titieds away
all these peptides floating about doing damage.
The amyloid pla has lost favor being the primary damage.
Now people more interested in lowering the levels of abeta in brain so you never form a
plaque. Immunization might actually stick on the plaques and cause them to be eaten up,
may lower the level of abeta, and lowers plque formation.
Talk to people at Elan and they say new drugs you can always expect side effects.
Tangles largely ignored because they were thought to be secondary effect. Also, inside
cells. Plus hardly worked on by anyone so not much known.
What’s happened to people who were vaccinated is that you’ve cleared some of the abeta
but left the tau tangles. So you may have to target both.
We see a plaque and the damage may have been done 20 years ago. The challenge is to
find a drug that is safe and very well tolerated that you’ll start taking prophylatically
when you’re fifty.
You may not even have a genetic screen. Like statins. Anyone can get them, even
without high cholesterol.
Seven people in her lab.
Ended up working with rpm—symbiotic. The geneticists want their findings to be more
than a gene on a piece of paper. They want to look at its fundctionlity, want to see it
really does cause disease by putting it into animals, so R needs me to put the genes in the
animals, and I need someone like him to give me the genes to put into my animals model
to see what they do. It’s all part of a multi-part process. Finding the gene is just the first
bit.
Long term collaborator is John Hardy. But hardy not really working on it. A lot of effort
for not a lot of reward. The families don’t have the power any more to generate the
mutations so really a new mutation hasn’t been found for years.
If a new mutation were found, would it be significant: Yes, definitely, it would open up a
new pathway for us to see if it’s affecting amyloid, tau, is it anti-oxidant, is it cholesterol.
The trouble defining when was found is difficult, because they are found, but it’s not
clear that they are real disease-causing mutations. They’ve found polymorphisms, but
not disease-causing. Pms are sometimes very interesting, apoe, that was huge. That’s a
case where it’s a normal variant, but it’s more likely to give you the disease.
Apoe increases your risk. A mutation will usually cause a disease, if it’s fully penetrant.
If you have a variant you are often more likely to get it but it’s not guaranteed.
Apoe 2, 3, 4 and you can have all combinations and if you have 4/4 you’re pretty much
guaranteed to get it. If you have a 2/2 you’re pretty much protected.
Polymorphism is not a mutation, it occurs naturally, but if you have the unlucky
variant…
Can’t see plaques and tangles yet with imaging. Are starting to be able to see plaques in
mice images
Mouse brain the size of chickpea and have a lot of signal to noise. Shows me pictures.
The mice with plaques—they look spotty. They are everywhere. Strictly a model of
amyloid formation, not AD, because mice don’t get AD.
Now working with a rat model—rat with AD.
The brain of mouse is smooth, not wrinkled like humans.
You can create plaques and tangles. First do them separately, then breed them and they
pass both to offspring. That’s the power of a genetic model.
Mouse in the water maze=Karen’s mice.
They use visual clues around the room to figure out where they are. That’s the memory
part. If they are demented they don’t remember.
Rodents love chocolate. Also granola bars.
Motivation in water maze is that they don’t like cold water.
How do you know a mouse is demented? it’s subtle, yeah. They have to be motivated.
You can motivate them with food, with fear, giving a little shock in their foot, and can
test memory, and the ability to learn. What is relevant to AD is a little bit difficult. It’s
retention of short term memory. Tryng to model that in a mouse you have to try to
model the right thing and part of that depends on circuits. You can have the same disease
defect [ie. Tangles or plaques] in different parts of the brain and they give you completely
different behavior.
When mice have cognitive impairment that’s linked to an increase in abeta or an increase
in amyloid plaques
You hear people talk about amyloid and amyloid plaque and that’s catch-all. A-beta is
probably more dangerous than amy.plaque. when there’s too much it probably causes
plaques.
Other markers before abeta is a tau marker when you combine them you get almost 90
percent specificity.
Blood based markers weak, unlike csf, which comes from the brain. Getting csf is
invasive and potentially dangerous procedure. In Sweden used more regularly.
Richard’s study important: because such a big family, the power of numbers, those
families don’t exist anywhere, like those smaller island nations, like Iceland.
There is an Icelandic mutation.
African American population doesn’t have the apoe variation, tell you that there is
something compensating for it. Very interesting to find out what that is may be useful
theraputic.
Richard’s finding: it will be universal because a genetic mutation, which is penetrant, not
a polymorphism. What he has, instead of being this far from the gene, he can get this far.
What happens between people is the bits of your chromosomes cross over and swap, bits
of genetic material are swapped. If you know that something is at point A, and you have
a piece of dna and it crosses over you can’t get to point B because it’s moved. So what
you want is no crossover and then you can get very close. What you have with people
who are very closely related to each other is that they have far less crossovers.
It’s all about what’s shared between patients who have the disease gene and those that
don’t.
There are different times when you want to change the dna and when you don’t.
There are three million base pairs of dna and some are clustered in areas and some are
gene free
If you have a known point and an unknown mutation somewhere in that vicinity and you
want to get closer and closer to that known point until to that mutation till you’re right on
it.
Known point is like a flag. You know where they are. A marker for where you are in a
chromosome. They were worked out in the genome mapping. These are called SNIPS.
It’s a bit of dna that we know where we are on a genetic map. It anchors you. If two
people who have AD have the same snip then you are probably in the area where they
share a piece of dna that has the mutation.
One you get really close you can see the base change. You could be millions of base
pairs away from the mutation but be on the same chromosome. We have to creep closer
and closer and closer. That’s why people who are closely related people who have the
disease have the power to let you get closer and closer and closer because they have more
shared information. It’s easier to find things that are common.
It’s physical. You’re looking for sequences of base pairs. Done on computer. Gives you
amazing accuracy.
Marker not necessarily a gene, usually doesn’t have functionality. It’s like knowing
where Wilmington is and saying it’s in Delaware. You don’t have to know anything
about Wilmington to know where it is. And then you can say we’re twenty miles from
Wilmington, or I know the next town is whatever and I know it’s closer than NYC is.
Yeah, you could look at it as stops along a train line between major cities. And you’re
trying to find the one little town where the action is. That’s where the mutation is.
Everything is a genetic disease. Everything is a genetic disease. Genetic means two
things: some people use it to mean inherited and some people use it to mean a dna-based
change. Most disease are caused by a change at the gene level, not at the protein level.
Prion disease is not a genetic disease it’s a protein change. Most diseases caused by
something disregulated at dna level. Doesn’t mean it necessarily a mutation. Could be
transitory. Usually about something being up or down regulated inappropriately.
To me, saying AD is genetic isn’t meaningful. Because then people think it’s inherited.
Which it isn’t, necessarily. Most cases are sporadic. Now they may be genetic.
Susceptibility genes for them might crop up, like apoe. They may find them, but for the
moment, sporadic means of unknown origin.
We are hoping that the sporadic and the familial are linked. By the same pathway. So far
it looks like they do. The causes converge, even if they start very differently.
On the pathway that leads to AD amyloid plaque formation part of that in most cases
though you can hear of people who have a lot of plaques but no disease. It’s hard to
know what that means.
In theory, if they don’t have tangles they don’t have AD.
One of the good things about AD is that we probably don’t need a blockbuster drug. We
probably need a number of small improvements to delay the onset of the disease by five
or ten years. If you could delay it it would be amazing. The incidence of AD would go
down significantly. And that should be possible. It may be as easy as getting people
away of exercise and diet. You may begin to see a delay in numbers. Or preventing just
one part of it, like aggression, that would be huge. I see a lot of hope in Alzheimer’s.
It’s really important that people understand that.
When I was 16 I went to my first seminar at school on genes and I always thought
physics would be great but I can’t do the math. But I always had a leaning towards
biology but found bio unsatisfactory because it was so wishy-washy. Went to this lecture
and learned that you could change one thing in two billion and have an effect. And I said
that’s it. Then I wanted to take that one change and show what it did. Then put it back in
the organism prove it was right and show what orther pathways were invovled, and the
go on to treat it. Wanting to have something really solid to work with and to build out
from there.
I did general biology degree then did PHD in molecular genetics—moving bits of dna
around. Post doc in making transgenetic models. That gets very hard—the complexity of
the system, if you look at single cell, compared to mouse, compared to human. That’s
why you have to be very specific with what you’ve started. Because you can always go
back and say I know I changed this one gene and that set off this other things. If I have a
demented mouse that can’t get around the water maze, I have to know that that is because
I changed one gene. That’s hard.
I’m happy with mice. I think mice are a lot harder to work with than flies or worms, but
they are more accurate. They’re more like humans.