Alzheimer’s Disease as an Epigenetic Disease

welcome to the everything epigenetics podcast Dr Katz I’m excited to chat with you today thank you for having me yes so

you have a really interesting story as we were just chatting before we came on air um that I’m super excited to hear so

you know you’re a classically trained developmental genetic assist and your interest really lies in at first I guess

in the development of germline um of the roundworm seelan so you know I want you to go into this story I want you to

maybe you can even start with the end if you want to tell people your your greatest discovery and then how we got

there and um we’ll definitely go in and explain um you know what your evidence behind this this particular finding is

as well yeah so um you know my lab uh

actually set out to understand how hyt methylation can sort of function as

information and can potentially be inherited cell to cell and even um from

generation to generation and we were doing this in celegans as you pointed out um and the end of the story is um we

think that Alzheimer’s disease um is actually an epigenetic

disease in which a histone demethylase is inhibited um and it’s been a pretty wild Journey

as you can imagine going from trying to understand how hist methylation

functions in sort of transgenerational phenotypes um just as a very basic

mechanism to what we think is really major you know clinical insight into the

mechanism of Alzheimer’s um so that that’s the conclusion and I can tell you a little

bit about the journey yeah definitely I want to hear how you get from you know A

to Z you’re you’re starting to look at cagans as you know more of that simple model that people can can refer to and a

lot of those kind of initial preliminary studies or or pilot studies and now making this great statement as hey you

believe that Alzheimer’s disease is an epigenetic disease resulting from a a loss of sell fate so tell me how how you

got there so my lab actually there’s an intermediate step which is my lab also

studies Mouse um and so so you know we actually found some initial phenotypes

and celegans that suggested that hist methylation could be inherited transgenerationally and actually change

phenotypes um and so the C Elegance is really really good for that because the generation time is is basically three

days so you can have multiple Generations it’s a clonal it’s a hermaphrodite so you can clone out you

don’t have to mate there’s a lot of advantages for studying this um but when we found that I was really interested in

whether or not that actually might be true in mammals and whether or not there are inherited phenotypes due to um

inherited hisome methylation so my lab Works in mice and we went in to try and

understand whether or not um we are particularly interested in an enzyme lsd1 which is a histon methylase it

erases um this H3 K4 methylation which is a a hist modification which is

associated with sort of active trans description and we think that it needs

to be reprogrammed or erased between Generations because if it’s not it can sort of maintain transcriptional States

um and so we set out we we originally found that in celegans and we set out to see if that was true in Mouse and so

basically the very simple experiment that we wanted to do was basically delete this enzyme in The Germ Line Of

Mice and ask whether or not you could get inherited phenotypes from one generation to the next MH um we really

wanted to do that maternally in the in in female mice um but right away when we

started to do those experiments we realized that this histone demethylase if you go to uh Down The evolutionary

train um basically if you look at even down to plants or Yeast or um certainly

dropa it really is primarily involved in the germ line but right away in mammals

and in mice we saw that it was widely expressed in lots of different places including it was not just in the female

germ line but it was also in the in the male germ line so we had the

opportunity um to look in the male germ line and um we did that we actually very

early on discovered that this this histon methylase is involved in stem cells it turns out from many many Labs

that this histon demethylases required basically for all stem cells to differentiate so the population we

happen to be looking at were test stem cells which go on to make sperm got it um The Coincidence happens

because we were trying to engineer a mouse in which we could specifically delete this histone demethylase lsd1

it’s also known as kdm1a in mammals um in the male germine in the stem cells

and see what happens and we didn’t have the ability to do that so um basically

you do that through a technology called clocks and you have to basically have

the ability to have something that’s expressed specifically in that cell type we didn’t have something that we could

turn on specifically um in in the testes so

basically the long and short of it is instead of actually just deleting it engineering it to delete just in a male

Mouse in the tesus we actually engineered it where we could delete it everywhere so we could turn it off and

an entire Mouse and then we could actually just analyze what happens in the test and find out what happens to

those stem cells so we were actually taking an adult Mouse and we were

deleting the Gene and then asking what happens in the test but of course we were deleting it everywhere um and so

when we did that we got the huge surprise that within a series of weeks

um basically all of the neurons in the hippocampus and cortex all die and the

mice become paralyzed wow so that was not at all

what we expected it was not at all what we were studying um and it was a big surprise yes what’ you what did you do

at that point Sorry I have to cut in there what what were your your first initial thoughts and um well I I want to

get this answer and then I want to break down everything you just said for the audience just a little bit further but

um kind of what was that initial reaction uh stunned so you know right away I mean

immediately suggested that you need this particular enzyme in order to maintain basically the entire structure of the

brain um and and that was uh stunning um

not at all what I expected um because I expected it really potentially based on

everything we knew that if if if cells were dividing and changing what their

fate was like in a stem cell situation um you need lsd1 this hison methylase

but in the brain you have neurons right that are they’re not dividing um they’re

not changing their transcription and so it was

completely um sort of opposite of what anybody in the field knew about this

enzyme absolutely so uh no thank you for beautifully explaining that research and

that’s actually how I first really found you was this this work in epigenetics and Alzheimer’s and you know you have a

a couple papers as well where um you kind of talk about neuroepigenetic mechanisms and disease so um really

excited to dive into this a little bit further now I I want to back up my audience is definitely familiar with epigenetics if if you’re listening to

this podcast you should be by now um but more specifically DNA methylation as kind of that epigenetic modification so

when you’re talking about you know histone demethyl um can you just explain

that and relate that to epigenetics and then we’ll talk about the lsd1 en so basically whenever you’re talking

about um epigenetics um including DNA methylation you’re talking about um

changes that are not occurring on the DNA sequence but that actually can affect whether genes are on or off um so

a lot of times DNA methylation can do that directly but um in the case of hyt

methylation so DNA is wrapped around um basically like um you you would wrap

yarn around a spool or or a thread um and it’s basically packaged into what’s

called chromatin right and so basically you take a huge amount of DNA and you shove it into this tiny little nucleus

and to do that you can imagine that once you do that it makes it very very hard for Machinery to get in and turn on

genes so what happens is if you actually modify the packaging which is the

histones um then it actually changes the structure to sort of more open or

accessible or more closed and that uh basically helps facilitate whether genes

are on or off um so htl basically the

the this the series of modifications that occur to the packaging wherever that particular Gene is can actually

have a big influence on whether or not the gene is expressed or not so just everyone listening again to reemphasize

that it’s just going to be a different epigenetic modification one that we don’t hear about as often in regards to

everything I talk to but one that is obviously equally as important which is why we’re discussing that today so you

know this this podcast episode is going to be a little bit more mechanistic based but I want everyone to stick with

me here we’re going to keep talking about these connections for epigenetics hisone AC acetalation and you know how

that interplays with DNA methylation and just epigenetics generally itself we’re also going to get into some testing

methodologies how this will hopefully be commercialized or the applications and it’ll you know um to scale kind of like

the DNA methylation is now so Dr Katz going back to that lsd1 enzyme um what

if we know about it before did we know anything about it before you started kind of um taking a deep dive and then

why did why did you choose that one as well to um you know knock out um so I should one thing I should

add so if if the audience is more familiar with DNA methylation so um the

enzyme actually that adds DNA methylation is a complex called dnmt3 3 a and 3B and that actually um there’s a

direct uh basically interaction between hist methylation and DNA methylation

because that actually complex um actually lands on the packaging in order

to be able to methylate DNA so if if the histone where which the packaging is

actually methylated at K4 it will actually block um the DNA methyl

transferase from Landing there so when you have histone methyl it blocks the

DNA methylation directly so there’s actually an interplay between the hiso

methylation and the DNA methylation in terms of epigenetics so that that’s one thing um perfect as far as um

lsd1 um you know when we started actually down this road in mammals there

was only one thing that had been known which is that it was act absolutely

required so there was a mouse knockout made where they deleted the Gene um and that dies embryonically so that just

says that it’s required um that was the only thing that was known um and the

reason why we got into it actually goes back to a very very specific thing in um

seans there’s a particular moment where the two cells that are going to go on to make the sperm and the Egg they actually

lose this particular modification and so we wanted to know was this enzyme the

enzyme that was doing that the answer that that turned out to be no so you know I did a very simple

experiment um back when I was a postto basically in seans asking whether this his histon demethylase was demethylating

this particular hytto modification at this chemo the answer was no um but

actually what was interesting at the time is and what got me into this whole thing is that when you deleted lsd1 in

worms what happened is the population of worms actually got more and more sterile

over generations and that first got me interested in the idea that well maybe

the actual hypomethylation is changing over generations and is actually causing the phenotype so that’s where it all

started yeah very interesting no um I like to always hear how how these experiments get started and it seemed

like you had a lot of questions beforehand where you know you kept getting the answer no no no okay let’s let’s try this so started a long way

from where we ended yeah just kind of kind of the nature of of research right

um so okay so so we’ve done this you’ve you know knocked out the lsd1 enzyme and

and cgans you said okay maybe um as a result over time you know those models ended up becoming more sterile um and

then you’re knocking it out in mice and then we’re seeing massive neurod degeneration paralysis um you know

hopefully this is showing it’s leading and and playing a role in Alzheimer’s disease so how do you make that connection if you know you have you

knock out this enzyme you see these mice how are you then taking those vi and connecting that to Alzheimer’s disease

yeah I mean to be honest so I get this question all the time what why did you think that lsd1 was involved in

Alzheimer’s disease and the answer is I never did million years including even after

we actually made this we engineered this mouse where we got rid of lsd1 and an adult Mouse and we saw that it got

massive nerded generation I still had no no inclination whatsoever that it was

going to be evolved in Alzheimer’s disease um or any nerd degeneration at all um but it was just simply too

interesting not to follow up um so basically the way we first got to

Alzheimer’s disease so this this histon dylas it erases a hytto modification

which is associated with actively transcribed genes so it’s a repressor it turns genes off um so we simply did a

basically experiment we said all all right in all of these neurons that are dying in the brain what are the genes

that turn on when you lose it where the idea was could we identify some of the

pathways that might be between you know losing lsd1 and causing nerd

degeneration so we identify genome wide in the entire genome what are the genes

that activate when you lose this enzyme and you know as as you do when

you do this sort of genomic experiment you simply say all right well you know what kind of pathways are affected um or

does this look like any other experiments that people have done in the past and when we started to basically

search in the computer and look for this what it turned out is that the genes

that turn on when you lose lsd1 in a mouse look very very similar to the

genes that turn on in human Alzheimer’s patients okay so that was the first time

that we had any inclination that this could be involved in in a human disease at

all yeah and did you mention uh two points Dr Catz did you say there was another Point as well no I that that

that was that was the right um we basically we just wanted to know why

when you lose this this enzyme why did n die and and it turns out that the genes that turn on when you lose these enzyme

are really very very similar to the genes that turn on inside the brains of

Alzheimer’s patients gotcha and did you say you did that through a gws jome wide Association

study it was a simple RNA seek experiment um so we basically identified

gene expression changes genome wide um and um and then we just compared it um

using you know initially just geneontology and which is just a fancy way of saying what pathways are affected

and and basically through the computer you can you can ask in any experiment that

people have looked at Gene Express and changes do they match what you see and basically the computer can say yes this

looks very similar to what was seen and it turns out that you know large consortiums you know we starting to say

all right are there any important gene expression changes that are occurring in Alzheimer’s you know patient so they had

collected hundreds of specimens from deceased Alzheimer’s patients who had

donated their brain and they had asked all right what are the genes that turn on in these Alzheimer’s patients and

they had published a huge set of of genes and and the interesting thing

about it is the genes that turn on in an Alzheimer’s patients don’t make any sense to anyone there’s all kinds of different

Pathways and people argue about you know is it one or is it the other is it all of them that’s causing the disease and

so actually for the Alzheimer’s patients or for the Alzheimer’s researchers

you know it didn’t actually help that much to know because there’s so many different things um yeah yeah no no no

super super interesting as well I don’t think I’ve mentioned this on the podcast before but Alzheimer’s dementia definitely runs in my family you know

I’ve had family members you know loss due to the disease and it’s just it’s just heartbreaking so this is super

interesting to me from more of a personal level too I know I have the ap34 variant and um I’m also the type of

person who wants to know everything about myself so there’s anything that I can do to map my epigenetics to map my

genetics understand my disease risk how I can you know hopefully decrease that risk too I’m definitely all about it so

um Alzheimer’s itself is uh is actually interesting because people have um you

know look very hard for strong you know genetic correlations so there are there are two sets of of genetic contributions

to Alzheimer’s disease so there is a very very rare set of uh patients that

have mutations um and if you have those mutations you’re guaranteed to get Alzheimer’s disease U familial forms in

your very very young 30s and 40s um this is exceedingly rare um and then the vast

vast majority of Alzheimer patients which is exceedingly prevalent you know in in the western world and in the

United States um are basically sporadic so um there’s not a lot of evidence that

it’s there’s much that’s inherited at all the only exception to that is what you were talking about so apoe um is a

particular Gene and there’s a variant in it if you have an apoe4 um if you have two copies of that

in particular even there you’re not by no means guaranteed to get Alzheimer’s

that’s the only thing that will substantially increase your risk those patients tend to have not just a family

history but um a family history where people got it particularly early so most

people Alzheimer’s disease you know something like 75 80 85 and sometimes if

you have a large number of people in your family have gotten it a little earlier like 60 65 then sometimes you

can be carrying that particular variant you can get tested for that um you know on 23 and me or any of the other tests

um yeah again that’s very rare um even those Al those particular variants of

those genes are very very rare so the vast majority of time even if both of

your parents had Alzheimer’s disease you’re really not much above the the the average risk in the population well

that’s good to know that’s good to know that that’ll make me sleep better tonight I know that’s for sure um so

yeah Dr Katz again wealth of knowledge really um this I I Love Your Story from

beginning to to end and it’s definitely not not the end quite yet we’re still learning what this this all means so um

you know before we hopped on we were chatting a little bit about how we best wanted to to format this for the listeners and you mentioned that you

know a lot of epigeneticist are very supportive of your work yes you know green light this looks great but you

said more people within just like kind of the Alzheimer’s I guess research Community are a little bit more hesitant

or skeptical can you maybe explain why and yeah you know what’s the evidence what what are people asking what are

people wanting to know here yeah so I think that the that uh the reason why the Alzheimer’s field is so skeptical is

that there’s been a huge history of people coming in and saying oh Alzheimer’s disease is really this or

really that and um we’ve been studying you know Alzheimer himself identified

the very first um misfolded proteins in the brains of of human Alzheimer’s

patient um that was over 100 years ago right so we’ve been studying this disease for a long time right and and

you know you would think with all the number of people and now the huge amount of resources going into it that we would

have a lot of insight and we have you know learned a lot I I I’m not going to

downplay that at all but there’s a history of people coming in and saying Alzheimer’s is really this and it’s

really simple and it can be cared or whatever and and those things have not turned out to be true um so I think

people are pretty right to be skeptical um that being said you know I

think one of the things that’s not so great is I think as scientists you know you want to be skeptical always and we

were very skeptical ourselves and then you see whether or not the evidence actually can change your mind right so

once you have a certain number of pieces of evidence and I can go through um what we have now subsequently been able to

show um then I think you start to change your mind right and I think the epigenetics community has been more open

to hearing look you’ve got all this evidence that suggests um that this enzyme could be involved um whereas the

Alzheimer’s Community I think is a little more well we’ve seen it all before and so nothing can really be true

right right I think they don’t want to get their hopes up right we’ve seen a lot of those I I don’t know even if if

you want to talk about this as well or and you’ll be able to do this better than myself but some of those falsified you know images with the Alzheimer’s and

you know thinking we’ve made a really big breakthrough you’ll see kind of I I’ll see at least in my Google alerts or in the news hey something new or you

know we found a partial cure or something right and then something else happens so um yeah to you know tell me

what else people are saying and then I I do want to hear again your evidence for um to support this yeah I mean even

currently right so there are two drugs that have been approved U very very recently um and there’s a lot of

controversy surrounding particularly the first drug but even both drugs because um the second drug that looks a little

bit more promising even there you know to say that it really is an Alzheimer’s

drug is I think um maybe overreaching a little bit

because it doesn’t modify the progression of the disease at all right so the people even if you take the the

drug and even if you say it works in the trials that the people still get degeneration they still progress the

same what it does is that it slightly modifies symptoms in the very early

phases of the of the disease so um and it’s questionable in my opinion anyway

as to how much it really would really notice the amount that it modifies it obviously if you give people cognitive

test you can test it and it’s a Bally significant and I don’t want to downplay that at all it is our first drug that

does anything to the disease so that’s uh a fantastic thing um but we are

nowhere close to having anything that you would describe as as a cure because none of these things even uh none of the

drugs even claim to modify the progression of the disease so um you know if you if you have Alzheimer’s what

you don’t want to do is have your dementia progress and lose all of you know all of the the things that are associated with

those patients which is starting with short-term memory and then leading to you know really major major cognitive

defects um so um you know as far as what

we found is you know so so once you um once we found that the genes that are

changing in our mice were very reminiscent of the genes that are changing in the human patients um the

first thing that you might want to know is all right well is there any evidence that lsd1 itself this enzyme that that

we were studying is affected in human Alzheimer’s patients um so obviously a mouse is not

a human and and so you know you don’t want to make a claim about the disease

in a human unless you have any evidence that it’s affected um the interesting things so just to give your audience a

little bit of context about um human Alzheimer’s disease

and I I will join the lay people in saying that I really knew almost nothing about Alzheimer when we started this so

um I’ve come a long way obviously but um I knew very little so there are two

different proteins um which misfold in the brains

of Alzheimer’s patients so they are called um beta Amid and to and actually

in the very original drawings um from Alzheimer’s himself from the very first

patient you can actually see that he drew these so what happens is you can see in these patients that there are

proteins which you know for the lay audience is basically the building block of the cell everything is made out of

proteins so they normally have a particular structure and what happens in the case of these two particular

proteins only in Alzheimer’s patients is that they misfold so that they lack

their normal structure okay and so those two things we’ve known

for a fairly long time correlate with the disease so you tend to see them

inside the the the patients brains U who have Alzheimer’s disease um we now know

I mean for a long time there’s been a lot of people focused on beta ameloid because and quite rightly so because the

beta ameloid you know hypothesis if you will came about when first of all people

identified one of these proteins was beta Amid and then very quickly thereafter they showed that if you have

familial mutations that affect beta ameloid that those people get Alzheimer’s guaranteed in their 30s and

40s these are the very rare patients that have mutations so that was pretty

good evidence right so you have you have the the patients have the misfolded protein and if you have the mutation

that’s in the pathway you get Alzheimer’s disease so you say look finished done right that’s got to be the

whole disease right made a lot of sense just one part it’s just one part though right is what you’re is what you’re

getting at here it turns out that there was very there’s another misfolded protein Tow and and yep um there one of

the things that happened right away that should have been maybe a clue is that there’s a lot of people that have misfolded beta ameloid that don’t have

all Cy’s disease so there is an overall correlation but the correlation is not

by any means perfect um now as we’ve gone on fur further there is a better correlation

much much better correlation between misfolded towel protein um and so now

there’s more there’s sort of a revised beta ID hypothesis that basically you

start to get misfolded one of this one protein beta ID later on you get misfolded Tow and that

eventually one or both of those proteins probably to but maybe some contribution

of beta ameloid are actually interfering with something that the neuron need needs to do and causing the neurons to

die so what really happens in Alzheimer’s disease is you get millions and millions of neurons that die okay

and that’s why you get dementia gotcha so the big question is how in the world

does to for example cause a neuron to die

yeah and that and that’s what you found a little bit with your uh study is that correct right the interesting thing is

going back what I said is so as soon as found this we said all right is there any evidence that this histone dylas is

affected in human Alzheimer’s patients so we went in and we looked at this this

particular protein lsd1 in Alzheimer’s patients and one of the things that’s been really frustrating for the field is

that even though like too is supposed to be killing neurons and and and causing

probably Alzheimer’s disease right people have said all right it’s interfering with things inside the cell

so what are the other things that are basically getting stuck when these proteins misfold so people have looked

very very hard for other proteins or other Pathways that could be affected um

you know and and basically it’s been exceedingly frustrating nobody has basically found much of anything there

are a few things that have been found but um not a lot so we were again

floored because we went and looked at this particular histon demethylase and it’s normally in the

nucleus because it has to regulate genes and and the buildup of this misfolded

tow actually happens basically in the cytoplasm so they’re in different locations but the moment we looked

inside the human Alzheimer’s brains we found that this hison methylase was

basically perfectly localizing to misfolded tow gotcha okay perfect so you yeah oh

that is exciting I can’t imagine so you you found this pathway way Dr Katz and

then you you know you’re were super surprised kind of with these findings and relating it to Alzheimer’s disease so when when did you actually make the

discovery with the tow protein so that happened you know it’s funny because um

we we had the original this Mouse project and we showed that you get nerd degeneration and we wanted to publish

that and actually people said oh you know you should look to see what’s happening in the human patients and I

said well that’s going to take us you know years I knew a little bit in the digging into literature even a little

bit you know was very difficult for people to find things um so I was very hesitant to do it but I got pushed by I

happen to be at Emy University we have a very strong Alzheimer’s group we actually have um in for the whole

Southeast of United States one of the only um brain Banks where people can donate their brains if um if they have

Alzheimer’s disease so we had access to the patient samples um and so it wasn’t

that actually hard to take a look at this and so it turned out I got pushed

to do it and we did it and I was shocked because it was so obvious so basically

what happens in in Alzheimer’s um disease cases it’s called so once the people die they donate their brain and

then they do pathology which is basically an autopsy and they ask um do

you have this misfolded tow in your brain and and and mostly do you have misfolded beta ameloid in your brain so

so technically you can’t be diagnosed with Alzheimer’s until after you die because the only way we can really prove

that you had it is to look inside the brain and look at these so people get diagnosed with it but actually to prove

it and to be considered a true Alzheimer’s patient um then you actually

have to donate your brain and be diagnosed that way um so um in any case what’s

interesting is so you diagnose this by looking at this toab protein and it turns out that if you use the same exact

technique and you look at lsd1 instead of too then you can take the people the

Pathologists who are the doctors who actually diagnose this and they can’t tell the difference so they look exactly

the same which was huge surprise the lsd1 and the tow protein you’re saying

yes yeah yeah and and you know what that’s that’s great that you have that kind of brain brain bank if you will at

Emory I think the University of Kentucky here does that as well I know we have some really good Alzheimer’s fastic Alzheimer group and they also

rain bank for sure yep yeah yeah so um yeah I mean that’s that’s great did you

in what year was that or when was that when you started look notifying that kind of in in in the human brain as well because that’s my next question is hey

how do we take this from the SE again to the mouse to the human what’s the what’s the translation to the humans what’s

that relationship but pretty strong we first made the discovery um the first

time we saw that the mouse was getting near to generation was basically in

2013 um we published our first paper I think in maybe

2017 something like that um showing the first uh you know and that included the

first evidence that it was actually could be affected in the human patients and you know now we’re in 2023 and we

have substantially more evidence that I’ll talk about but um so it’s taken you

know maybe 10 years from the very very first discovery yeah um yeah yeah that that’s great I

was just kind of uh you know that’s I would say that’s not that long considering everything right it actually

moved pretty quick because I think once you kind of find that little uh you know Golden Nugget if you want to call it

that and then kind of take it and and run with it like you said when you looked at those human brains you saw the um you can tell the difference between

the lsd1 and the towel so this is great and and do you think that this could act

as a way to diagnose Alzheimer’s in patients beforehand like how how are

they um you know doing these clinical trials with all of these drugs if you can’t technically diagnose Alzheimer’s

you know when they’re still alive or that’s that’s hard so we now in the in

the last um just couple of years have figured out way through scanning um to

actually you can identify the build of a beta amalo and Tow in uh a human bin

brain in a live patient um got it that can actually be done ahead of time now it’s very people don’t do it very often

because it’s a you have to take a compound and insert it into your bloodstream it goes everywhere and then

they do imaging it’s it’s it’s a it’s not an easy procedure so okay um it’s not done that often but it can be done

uh okay um yeah so and and as far as you know for a lot of these these

experiments and things are are the way people have done it um you know it’s

actually you know for example the the clinical trials for these drugs that have just come out um it’s actually interesting

because you know the inclusion criteria are difficult because you get included based on the dementia which is basically

you say you’re having short-term memory issues but um and I the good clinicians very easily can tell the difference

between for example um uh Alzheimer’s and let’s say front to temporal dementia which is the second most common form but

um it’s not perfect actually yeah relies on on and sometimes they’re wrong right

so um there are people maybe in those clinical trials it’s possible you could have a small number of people who

actually don’t have Alzheimer’s yeah I think so I think I think that just that just can be be hard but you know

hopefully with this new Imaging and then you know we’ll have better stuff in the future I’m sure as well um so so yeah

did you mention that you had some another piece of evidence you wanted to talk about Dr Katz yeah so you know so

the first two pieces of evidence said all right the in the human patients it’s a COR which just says right we know that

there’s this protein which misfolds which people think might cause Alzheimer’s we know that this hend

methylase is there where it’s not supposed to be and so then it means it could be affected it doesn’t say that it

is it says it just could be affected and we know in the in a mouse model that if

we actually just get rid of this enzyme we can cause nerd to generation so that’s causitive right those are two

pieces of evidence but the big missing piece is all right there’s no connection

is there any evidence that actually too can truly block lsd1 that it can inhibit

lsd1 right so basically um so the model is so lsd1 is a protein which regulates

genes in the nucleus and to is a protein which misfolds in the cytoplasm of these

neurons and the model is a pretty simple one which is to say that this this

enzyme lsc1 is supposed to be in the nucleus it’s getting stuck in tow it can’t get in the nucleus where it can’t

repress genes and that’s causing all of these different you know Pathways to activate that’s the model so the

question is so that model makes a couple of different predictions right so it suggests that if if the main way the tow

is actually causing problems is by inhibiting this enzyme that you should be able to manipulate that right so you

should first of all you should be able to show that to can maybe prevent lsd1 from being in the nucleus and you should

be a to say all right if that’s true if you were to reduce lsd1 let’s say in a

tow a mouse model it should make everything much worse right because it should be much

easier for lsd1 to get stuck and if you were to actually increase the amount of

lsd1 in a to Mouse model then potentially even if some got stuck some would still get to the nucleus and it

might actually you know help so that’s what we set out to do is

we set out we took uh a towel Alzheimer’s well I shouldn’t actually

call it an Alzheimer’s Mouse complicated because to the towel mutation actually

came from a front to temporal dementia patient so it’s really a towel model you know to mouth model but anyway so if you

take a to Mouse model and you say all right

um if the prediction should be that if you reduce lsd1 in that Mouse model it

should make everything much worse and if you increase the amount of Elsy one it actually could potentially make things

better um and so the town model we should say is a little bit you know I

don’t know if controversial is the right word but it it it the town mice never get nearly as severe as human patients

um and it’s not really known why maybe because the mice don’t live as long as a human patient so it takes time in any

case in the to Mouse model basically they’ve been engineered for to this

protein to misfold and they do get some nerded Generation Um in those mice okay

I’m following I’m taking a lot of notes but but I’m following here um and and I guess to cut in Dr Cat’s point being is

you can’t knock out the lsd1 in humans that’s not that’s not possible right so you’re you’re you’re doing kind of

you’re taking the Alzheimer’s model from a human and trying to replicate that in the mouse by using that tow protein and

we’re just not maybe getting as a clear picture as we want quite yet to scale so

that’s what so that’s what the to model is so what we did is we simply took the T to Mouse model and we said first of

all can too actually block lsd1 from being in the nucleus that turns out to be completely true so if you look in the

tow Mouse model lsd1 which is supposed to be in the nucleus it now is completely gone from the nucleus in

those key neurons so that was great um and so now it’s no longer just a

correlation but we actually show the to can inhibit lsd1 and then we said all

right if we reduce lsd1 in the to Mouse model it should get much worse that turns out to be very true so what

happens in the to Mouse model is to misfolds over six to n months and then

they get nerded generation around a year it’s not so severe as I said but if you

reduce lsd1 just a little bit even by 30% those mice once the tow starts to

misfold they get a way more severe version of nerd degeneration that actually looks a lot like the human

patients now for the first time so it makes things much much worse okay well and if you cre increase

the lsd1 are we in the nucleus for tow are we seeing those mice get better yeah so we did that and we did that in a

particularly I don’t know the right word is but maybe in aggressive way which is we said look so there are people who

have been able to modify the tow Mouse model so they get less nerd degeneration but those are typically modifications

from birth so genetic modifications and things we decided look if we’re right

and lsd1 really is the the thing that’s causing nerd degeneration and in by to and in the human patients then we should

be able to increase to not just from birth but right after the to excuse me

increase lsd1 not just from birth but right after Chao has already misfolded basically

equivalent to the time that you would walk into the doctor’s office as a patient and that should actually have an

effect so we did this in a fancy way we engineered the mice basically so that we could actually increase lsd1 in the tow

Mouse model after they already have tow that’s misfolded just before the neurons

start to die and we were able for the first time to block neurons from dying

oh wow wow awesome that’s a million-dollar question then right can inhibit lsd1 we see it go up do we get

better if we see it go down do we get worse and again I would call myself we definitely more of an epigeneticist than

an Alzheimer’s researcher but the evidence seems you know pretty strong for for me

at least so where where do we go from there Dr Katz you know how does this work advanced Drug Discovery and

Alzheimer’s disease um I guess like what what are you working on now it seems like you’ve proven kind of all three of

those points in a mouse model again I don’t know how much more you can do or show do you move to a human model how

does yeah it’s difficult you know once you get to a certain amount of evidence that um there’s not a lot left to show

except for whether or not doing the same thing in a human can actually block nerd generation right and to do that you

actually need a drug you can’t engineer the the humans like you right right so

um so we are very interested in identifying a drug we are current

um starting on a drug screen um to basically find this so again the model is a pretty simple one which is we think

that to when it’s misfolding is blocking this this enzyme that has to be in the

nucleus repressing genes and it’s blocking it it’s getting stuck so it’s not there in the nucleus and lots and

lots of genes are turning on um it’s interesting because it’s um from an epigenetic standpoint and that and we

can get back to this if you want in a minute um you know so what are the genes to

turn on why is it all these weird Pathways because it’s a whole bunch of weird genes it almost looks like the set

of genes that are easiest to turn on in a neuron that this is normally blocking

and and it’s a it’s a bunch of very strange genes but it causes a number of different Pathways to turn on and those

are all the same Pathways in that you see in the human patients and those Pathways a number of which are probably

all killing the neuron um got it so we just think that it’s an

intermediate between to misfolding and the downstream Pathways that are killing

a neuron right now the sort of consensus is that you know maybe Tao is inhibiting

somehow inhibiting all of those Pathways we think that it’s really inhibiting a single Target that Target is normally

affecting lots of Pathways and so that’s how you get all those Pathways affected yeah know I mean this makes

sense I I I you know was so excited to talk to you but I think a little bit nervous to see you know if my my

audience could follow along here but I’m following very very well so we have this tow protein um it’s going to be one of

the misfolded proteins that happens in Alzheimer’s so um when this happens uh

well we we do c I said to inhibit the lsd1 we need the lsd1 to help regulate

our gene expression but when tow has an effect on this lsd1 it’s actually turning on a lot of genes that shouldn’t

be turned on thus you know Alzheimer’s happens will that be a good summary that’s of course I’m taking notes here

and trying to trying to walk through it myself but this is uh seriously groundbreaking work and um very very

excited to follow along so is that then again um your main priority right now is

to look for drugs that um are helping increase uh the lsd1 or something to

work on that pathway we have um we have that’s the main priority yes um the

other the only other remaining question that we have is why does LSD one gets stuck in tow when lots of other proteins

don’t um that’s a big question and we have some evidence for that it gets

pretty technical about what we’re talking about yeah about that but um

that actually is not necessary to know that it’s involved in in Alzheimer’s disease but I think it is an important

part of when when we’re evaluating the the drugs that come out of our drug screen um we so what we’re looking for

is a drug that can block this Interac ction between too and lsd1 and allow

lsd1 to still go into the nucleus to repress genes even when too is

misfolding got it yeah and and again to all my listeners this is really really important a lot of times you know we do

spend a lot of time on epigenetics and Longevity and aging and correlation correlation correl correlation which is

not causation but here we’re having both right we’re having hey tal misfolded protein um equals an effect on the lsd1

so that is the correlation the causation is hey if we actually not out this LSD one in mice they actually tend to have

worse outcomes too so this is is I know it’s more mechanistic I know it maybe you know again a little bit harder to

follow but this is where we can actually then go into this drug Discovery pathway and bring this bring this to application

and bring this to Market so um just just super super fascinating and uh I know we’re we’re getting close to the end

here I feel like I could talk to you all day Dr Katz I want to give you a second to talk about a program that you’ve

established with a nearby liberal arts College I think it’s uh ogal Thorp if I’m correct um called cure so would

would love for you to be able to promote that and even talk about how it helps uh promoting Dei and science yeah so um you

know going back to this the the beginning of this project right so we started this by doing um very basic

experiments on a tiny little microscopic worm um and trying to understand

transgenerational effects things that are passed on from parents to The Offspring um and what’s what’s really

great about the this this model system celegans is that um it’s very quick and

easy to learn right so they there’s a new generation every three days they’re very easy to take care of um they don’t

cause any you know any um there’s no health problems they’re found commonly

everywhere in the soil they’re in rotting fruit everything so um that

allows us to actually do something that I really wanted to do for a long time which is um to try to promote science um

one of the big problems in science is that there’s sort of an accessibility

problem right so so in order to be come a scientist a lot of people have to go

to pretty fancy universities that have a lot of money to put into this and then

on top of all of that um they have to really opt in so you have to be the kind of person who’s is willing to go

approach uh a professor like me and say look I want to learn how to do this and

and um you know for a lot of people that’s just not realistic right so what

and so what we’re doing is we’re missing out on a huge population of people who could be fantastic scientists so so what

we wanted to do is sort of bring science you know instead of an optin model

basically just a system where people would be exposed to doing research um

without having to opt in so we went to a small liberal arts college here in Atlanta that has a huge uh

underrepresented minority population many people are their first in their family to go to college and what we did

they was it’s a tiny little arts college so they don’t have any research whatsoever um no facilities but as I

said this kind of research doesn’t require a lot so we um we started this

actually with very little um we basically said all right we’re going to integrate short research experiences

into the entire curriculum right so this is what car stands for C is not specific

to our program ours we technically call it a pipeline cure because it happens over all of the time of college all the

different years freshman through senior but car just stands for course embedded U research experience right um so

anytime you take research and put it into the classroom in the context of a course that’s called a care

so what we did is we said all right we’re going to try to go beyond that and

we’re going to slowly introduce this system into early classes so the students there start to take you know

small research experiences two weeks you know just like you would have a lab in a class um and they learn the system and

then as they go along by the time they get to a junior or senior they can opt into much more advanced you know

research program s where over the entire semester they’re actually doing

experiments um and is actually some of these experiments have resulted in some

really amazing epigenetic um results where the students themselves have found really elegant

examples of transgenerational effects where you can actually have traits that

are passed on from one Offspring to the next yeah yeah know that that’s great um

and I meant to even say this earlier as well you know for anyone who’s like what’s the germ line what’s transgenerational epigenetic inheritance

which is a mouth W um I did talk about that topic very specifically with Dr

Michael Skinner in one of my last podcasts from Washington University that you can watch and then I also talk about

um I spoke with with the you know bringing Dei into science with actually Dr Kristen bird from Ohio State and I

just think it’s it’s so important I think the more we talk about it the more we can get people involved um because

you’re right you know I remember being a a freshman in college and being scared to go to Professor’s doors and ask for

you know research positions that you have to start off early in your career or you know you have to get in and then

that’s when you really get into some of the deep signs like you’re doing now so you know very much a big thank you I’m

sure to to everyone that you’ve helped there in that cure program and I’m excited to see where that goes and how it helps promote um you know your

epigenetics and and even the work you’re doing yeah one of the things that’s really hard is that you know if you’re

just if you don’t have a scientific background you may be a biology major in college by the time you realize what

research is maybe it’s your junior or senior year a lot of people have already been doing research before that you don’t know where to start so what

happens in this case is because they’re just doing it so in order to people say how do I get into this program all the

the freshmen come and ask there how do I get into this program and I said there is no program it’s just a biology major

right so any student who enrolls as a biology major gets this just whether they want to or not they they get the

experience they don’t have to into the research at the end but they all get trained so the point when they’re

juniors and seniors all they have to do is enroll in the next class and they

already have the training in background so there’s no op in here right no no

realization that they have to do it and go get the training on their own they all already have it um and what that

means is that that you know it sort of lowers the barrier to entry because you

don’t have to know that you’re entering the program until you find out oh I really like this yeah I mean that that that

experience is essential so just you know supplying it with people whether they want it or not they can choose to you

know leave it as is but um I mean that is definitely needed and and you know such a competitive atmosphere too

especially if you’re not getting any um of that uh kind of experience you know from High School which is very very rare

so um yeah excited to see that grow Dr Katz and hopefully be offered you know all all around the us or all around the

state or something we have for the first time this University is very old 150 years 180 years something like that and

basically as far as we know they’ve never had students go on to be a PhD or or become a scientist and we’ve now had

two go directly to PhD program so oh very cool yeah yeah excited about it

yeah and and we’ll only see those that you know that number increase as well so um yeah Dr Katz I have one last question

for you it has nothing to do with anything we’ve talked about so far I ask all my guest this if you could be any

animal in the world what would you be and why an animal yes oh it’s a he heavy loaded

question um uh I don’t know I love penguins they’re very they’re very cute and uh

you know um you know the idea of living in a you know particularly you know like

Antarctic penguins that live in these really really cold climates and and you know have no problem with that I think

that’s pretty amazing um yeah no one’s ever said penguin so

have you ever seen one in the have you ever seen one like in a natural landscape um you know not so much but

I’m actually I’m going on a trip to South Africa to see colonies of penguin so um in a couple of months be able to

see some which will be fantastic please please send me pictures I bet that will be beautiful I bet it will be

breathtaking too well um this is great Dr Katz you know for anyone who’s interested I don’t know maybe they want

to reach out about your um kind of offering or you know learn a little bit more about how to get involved in science or just your work in general

where can they reach you um you can uh easy thing is to find me on Twitter at

catore laab um or you can reach out to me um my email which is djc Katz atm.edu

or the website at if you just Google search David Katz Emery University um

you can find our lab website awesome and I’ll make sure to put all those links uh for those listeners out there who are interested

so thanks everyone for listening and keeping up with Dr Kats and I uh at the

everything epigenetics podcast remember you have control over your DNA so tune in next time to learn how thanks Dr Cat

thank you