Introduction

This live discussion was held on the paper by O'Doherty et al., in Science, on "An aneuploid mouse strain carrying human chromosome 21 with down syndrome phenotypes."

Lizzy Fisher and Victor Tybulewicz led this live discussion on 14 October 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Participants: June Kinoshita (Alzheimer Research Forum), Victor Tybulewicz (Institute for Medical Research), Lizzy Fisher, John Trojanowski (University of Pennsylvania), Rachael Neve (McLean Hospital, Belmont, Massachusetts), Muriel Davisson, Cindy Lemere (Brigham and Women's Hospital, Boston, Massachusetts), Hunt Potter (University of South Florida), Lary Walker (Emory University, Atlanta, Georgia), Barbara Tate (Pfizer Inc.), Jose Abisambra (University of South Florida), William Mobley (Stanford University, California).

Note: The transcript has been edited for clarity and accuracy.

June Kinoshita
Welcome, all, to today's chat. We're honored to have Lizzy Fisher and Victor Tybulewicz join us to discuss their fascinating new Down syndrome (DS) mouse model. Lizzy and Victor, could you briefly tell us what motivated you to try this approach?

Victor Tybulewicz and Lizzy Fisher
Well, complete ignorance of how ghastly it was going to be was the first thing that motivated us.

June Kinoshita
Was it horrifically difficult? What did you learn that you can share with us?

Victor Tybulewicz and Lizzy Fisher
But…we thought about creating a new type of model that got over some of the issues of having the genes from human chromosome 21 (Hsa21) split among at least three different mouse chromosomes. At the time we started this, it seemed as if it wouldn't be too difficult to transfer a human chromosome into embryonic stem (ES) cells, and then use standard techniques to create the mice. It only took about 13 years…

June Kinoshita
 Wow!

John Trojanowski
How much brain pathology have you seen in your new DS model? This was not clear from the paper.

Victor Tybulewicz and Lizzy Fisher
We really don't know in detail. As per the paper, we've taken only a cursory look at adult mice. Nothing done on neurodevelopment, nothing done in details on brain regions other than what's in the paper, that is, loss of neurons in cerebellum, and no obvious pathology elsewhere.

Rachael Neve
What kinds of pathology did you assay for?

John Trojanowski
But even a cursory look with a few classical stains or antibodies would reveal plaques and tangles if they are there, so any sign of AD-like pathology?

Victor Tybulewicz and Lizzy Fisher
We are very short of funding on this project (grants are being written all over the place, currently), so this is really why we're rather light in having a full analysis.

John Trojanowski
Okay, send us representative sections from various time points and we can get back to you within days with details.

Rachael Neve
But did you do any of the classical stains that John referred to?

Victor Tybulewicz and Lizzy Fisher
Just to save time, pathology assayed for so far is only what's written in the paper, that is, map2, neurofilament 200, synaptophysin, glial fibrillary acidic protein (GFAP), tau AT270, tau AT8, IBA1, bA4 amyloid. These were general reagents chosen by our histopathology collaborator, Sebastian Brandner. So, as far as we can tell at the moment, in 20-month-old mice, there are no signs of AD-like pathology, including APP deposits.

John Trojanowski
Well, you did the right screens, so I assume there are no AD pathologies.

June Kinoshita
You also did some electrophysiology, right?

Muriel Davisson
The Ts65Dn segmental trisomy mice don't show plaques and tangles, but with some special strains we find there may be subtle APP deposits—studies are in progress. (See also ARF related news story on the Ts65Dn mouse developed at the Jackson Laboratory in Bar Harbor, Maine.)

June Kinoshita
Muriel, that's interesting. In which areas do you see the APP deposits? Also, what stains are you using?

Muriel Davisson
Cortex, I think—this is a collaboration—it is a special antibody the collaborator has and I don't know what it is yet.

Victor Tybulewicz and Lizzy Fisher
Just to pick up on Muriel's point, often phenotypes can be pretty different on different mouse strain backgrounds and this is something we haven't looked at, partly because we only get Hsa21 transmission on an F1 C57BL/6 x 129 background.

Muriel Davisson
The same is true for Ts65Dn extra chromosome. We can only get viable mice and transmission of the extra chromosome on a hybrid background—B6XC3H. We have tried backcrossing to B6, C3H, and 129 backgrounds with tiny litters and no transmission after two backcrosses.

Victor Tybulewicz and Lizzy Fisher
Muriel, any idea why that is?

Muriel Davisson
I think there is too much extra DNA. I have three other unrelated trisomies and the smallest one is viable on B6 inbred—the other two are not.

Cindy Lemere
Hi. I hope to stay connected this time. I've missed much of the discussion. Unfortunately, I could not see the answer to my question regarding APP and Aβ reactivity by Western blot, ELISA, and/or immunohistochemistry (IHC). If you need a collaborator, I'd be happy to look at some AD markers on brain sections using a panel of antibodies and pretreatments that we have found work well in formalin-fixed, paraffin sections. Also, I noticed that your sections are 3 microns thick. That may be too thin to see much pathology for some of the markers. Any chance of getting thicker sections (or we could cut the sections here at our lab)?

June Kinoshita
Cindy, that's a generous suggestion. I hadn't heard about the thickness of slices being an issue of detecting AD pathology.

Victor Tybulewicz and Lizzy Fisher
Cindy, hi; thank you also for your generous suggestion. We'll sort out what we're doing and get back to you if we need help…and we may well do….

Cindy Lemere
Hi, Lizzy and Victor. Did you say earlier whether or not you see an increase in APP or Aβ by Western blot? If so, do you think immunizing the mice might reduce Aβ oligomers and potentially ameliorate the hippocampal-dependent learning and memory deficits? Or, do you think the cognitive deficits are unrelated to APP and Aβ?

Victor Tybulewicz and Lizzy Fisher
Cindy, sorry, we have not looked at APP by Western blot, but we do know that the human gene is expressed at the RNA level. Interesting idea regarding immunization, but we have no evidence for APP pathology at the moment. Do you think it might be there but not seen using the rather minimal stains we've tried so far?

Lary Walker
Victor, Lizzy, it's a fascinating model. Since the trisomy includes one human APP gene in the context of two mouse genes, you have (with regard to Aβ) essentially a wild-type human transgene at 50 percent of endogenous mouse expression. Generally, wild-type expression needs to be high to generate pathology. Do you know how much human Aβ is being produced? I'd be surprised if this level of human gene expression would yield Aβ pathology within the mouse's lifetime.

Rachael Neve
Remind me, please; do you see specific overexpression of APP in these animals?

Hunt Potter
I would expect no amyloid deposits unless the mouse were mated to a mouse expressing human APP. The most interesting would be a normal human APP Tg, but one of the mutants would be good, too. Is that in the works?

Victor Tybulewicz and Lizzy Fisher
We see human APP, so presumably we have overexpression from having the two mouse copies plus one human copy. It's not yet quantified.

John Trojanowski
I am not certain if Hunt is right on this point on crossing the mice since they have human APP on board, but one needs to check for Aβ levels, solubility of Aβ with age, etc.

Barbara Tate
It would be interesting to see the peptide profile (how much Aβ40/42, etc.) these mice have.

Victor Tybulewicz and Lizzy Fisher
Agreed; it would indeed be interesting to see the peptide profile. No data as yet.

June Kinoshita
Victor and Lizzy, to follow up on Hunt's comment, do you have access to human APP mice to crossbreed with?

Victor Tybulewicz and Lizzy Fisher
Actually, we'd like to ask the AD community a question: What transgenic or knockout mice should we cross the Tc1 mice to (and why)?

Rachael Neve
Hunt, could you clarify your comment? I don't understand why they have to cross it with the type of mouse you suggest. As John says, human APP is already there. Hunt, are you saying that we need to boost the levels even more?

Victor Tybulewicz and Lizzy Fisher
We have a possibility, through someone in the UK, of using transgenics we believe are carrying a wild-type APP gene. Unfortunately, we don't know the specific name of the strain.

John Trojanowski
If you do need to cross with other Tg mice to model AD-like pathology, there are, to paraphrase Mae West, so many mice and so little time. But seriously, the choices are numerous and it is hard to predict the best way forward since much of this is empirical, which I gather must have been part of the reason it took so long to generate these mice.

Victor Tybulewicz and Lizzy Fisher
Well, John, we would welcome your advice and perhaps further discussion on this point (i.e., what to cross the mice to), but we do recognize that it's empirical and hard to predict, perhaps, the outcomes of these crosses. Rather exciting, really.

Rachael Neve
To pursue the DS connection though—I'm not all that familiar with what can and cannot be done with transgenic mice, but would it be possible to selectively knock out human APP from these animals? Then you can see which abnormalities disappear.

Victor Tybulewicz and Lizzy Fisher
Rachael, yes. Part of the long-term strategy we had (very long-term, as it turned out) is to breed to candidate gene knockout mice, so we can make a comparison for zero, one, two, and three copies of any particular gene and the associated phenotype of interest. However, as Roger Reeves showed with craniofacial development (see Olson et al., 2004), for some phenotypes it won't be a simple dosage relationship, but will also depend on interactions with the rest of the genome—including other genes on Hsa21.

John Trojanowski
My suggestion would be to characterize the species of Aβ being produced from the human gene and do this over the lifespan to get a better idea of how to plan the cross with other Tg mice. This may help winnow down the choices since, if there are good levels of Aβ, you might want to cross with BACE-overexpressing mice.

Lary Walker
Tau transgenics might also be interesting. Any plans to look at cholinergic markers? There is evidence for deficits in the nucleus basalis complex in Down syndrome.

John Trojanowski
Good thought, Lary. So there is one vote to cross with BACE Tg mice and two votes for crossing with tau Tg mice.

June Kinoshita
A number of these mice are available through Jackson Labs.

Victor Tybulewicz and Lizzy Fisher
We had thought of tau transgenics, and haven't yet set up a formal collaboration to cross to them, but obviously this is of interest given the APP x tau double transgenic results. Regarding cholinergic markers, yes, this needs to be done, also. No data as yet.

John Trojanowski
Another suggestion, which entails a lot more work, is to generate mice like you have already but with an effort to identify the minimal and essential part of human chromosome 21 that is responsible for the AD phenotype in people with trisomy 21. But, I do not know if that is feasible in our lifetime.

Victor Tybulewicz and Lizzy Fisher
John, regarding partial trisomies (which we think is what you mean), there are now various labs, including Roger Reeves at Hopkins, all working hard to produce partial trisomies of mouse chromosomes—Muriel knows all about this as well—to try to define the minimal regions and thence genes for different DS phenotypes, presumably including the AD pathology phenotype (see, for example, Olson et al., 2004). Lots in the works currently from various groups.

Rachael Neve
That's pretty much what I was getting at, John, with the selective knockouts.

John Trojanowski
That is terrific and I look forward to hearing more, and while it may be awkward to get into a long discussion here on options for tau Tg mice, we can talk offline next week on this if you wish.

Victor Tybulewicz and Lizzy Fisher
John, yes, we'd love to talk further with you.

Hunt Potter
I would also find a cytokine profile interesting as [in] Down syndrome brains [they] are upregulated (from Sue Griffin's lab's work; see Mrak and Griffin, 2005).

Victor Tybulewicz and Lizzy Fisher
Hunt, regarding the cytokines: Could we have a little more information? Which cytokines do you think would be most interesting to look at?

Hunt Potter
We have been very happy using our BioRad BioPlex instrument that looks at a whole series of cytokines at once so as to get good relative levels. IL1 and IL6 would be particularly interesting.

June Kinoshita
Victor and Lizzy, how old are the oldest mice you currently have? Do you see age-related changes, for example, in the reduced hippocampal long-term potentiation (LTP)?

Victor Tybulewicz and Lizzy Fisher
The oldest mice we've looked at are 20 months old, and that was just for the histopathology. We have not looked at LTP in older mice. Should we?

Rachael Neve
What's the current state of the art regarding involvement or not of APP overexpression in AD neurodegeneration in DS, using natural human partial trisomies?

Muriel Davisson
We and other groups are combining Ts65Dn trisomy with various knockouts for genes triplicate in Ts65Dn. As June says, many of these knockouts are available from the Jackson Labs (see, e.g., Cataldo et al., 2003).

Victor Tybulewicz and Lizzy Fisher
Rachael, some years ago, Anna Kessling and I (Lizzy) published a paper about a woman aged 76 who had a partial trisomy and was mentally retarded, but did not have classical DS and, as discovered at aged 78 postmortem, did not have APP pathology (see Prasher et al., 1998). She was trisomic for the region below APP to chromosome 21q terminus, but not for APP itself. This isn’t particularly definitive data, but I guess sort of lends weight to the idea that having three copies of APP may bestow the DS AD pathology.

Rachael Neve
That's very interesting, Lizzy; are there any other such studies published that you know of?

Victor Tybulewicz and Lizzy Fisher
Rachael, not that I know of, but please check the literature!

John Trojanowski
To follow up on Rachael’s point, how close is the field to dissecting out the minimal region in chromosome 21 in humans needed for AD phenotype? Are there miles to go yet on this?

Victor Tybulewicz and Lizzy Fisher
We're not up to speed on AD and Down's, but as far as we know there isn't much going on, genetically, regarding dissecting this out in humans. There were reports years ago of another locus giving rise to early-onset AD that was linked to near APP but was not APP, but nothing has ever really come of this, and there aren't that many genes in that region of the chromosome.

June Kinoshita
Regarding the LTP question: Do others have any thoughts about looking at this in older mice? It seems to be one phenotype seen so far in this mouse that might be relevant for AD. If Bill Mobley were here, he'd want to know about impaired nerve growth factor (NGF) transport in the basal forebrain cholinergic system.

Muriel Davisson
June, you're right.

Victor Tybulewicz and Lizzy Fisher
We've had some very preliminary discussions with Bill (mainly along the lines of "do you have any money, and if so can we have some?"), so this is something we want to pursue with him further. Just a thought from us: We have the mice, but we're not AD experts, although we do have an interest in neurodegeneration. We would be interested in collaborations with you AD experts where we send you the Tc1 mice to look for the AD pathology of your choice, perhaps in the context of a sensitizing cross, and then we can follow through with the genetic dissection, for example, through creating knockout/transgenics, etc., to pinpoint individual candidate genes.

John Trojanowski
Since impaired axonal transport is implicated in several neurodegenerative diseases (for review, see Roy et al., 2005), it might be a good idea to check out fast and slow transport in the DS mice in ventral root or optic nerve.

Victor Tybulewicz and Lizzy Fisher
In another life, one of us (Lizzy) works on motor neuron degeneration and published on the positional cloning of a gene in a mouse that turned out to have mild motor neuron loss and a defect in the dynein heavy chain. So we have access to retrograde/anterograde transport folk over here and are planning to see what we can do on transport in motor neurons in these mice. Should we look specifically in ventral root and optic nerve, as well?

John Trojanowski
On transport methods, it is usually done by a pulse chase type experiment through injection of S35-methionine into eye or ventral motor neuron pool of the spinal cord, and then dissection of the nerves with axons emanating from these neurons to monitor rates of transport of newly synthesized radiolabeled proteins. Hence, my suggestion on the spinal cord and optic nerve.

Hunt Potter
Any information on karyotype appearance or on methylation of other chromosome 21 genes?

Victor Tybulewicz and Lizzy Fisher
Hunt, good point regarding methylation. No further information on karyotype (other than, as per the paper, each time we've looked, the Hsa21 has remained freely segregating). No information on methylation status. However, remember that there is mosaicism for the Hsa21 in all the tissues we've assayed, including brain.

John Trojanowski
Do you have a program/plan in place to examine other biomarkers of aging in the mice?

Victor Tybulewicz and Lizzy Fisher
John, what other biomarkers do you mean?

John Trojanowski
I am not an expert in general aging biomarkers, so I have no specific suggestions, but a review of AD biomarkers by a consensus group appeared in Neurobiology of Aging, from which you could make selections (see Frank et al., 2003).

Rachael Neve
Given the recent data strengthening the idea that cell cycle entry is part of the AD pathology (see Yang et al., 2001), it might be interesting to do bromodeoxyuridine (BrdU) studies with the mice to see whether DNA synthesis is occurring in any part of their brains. Or you could begin by immunostaining for upregulation of cell cycle proteins that are upregulated in AD.

Victor Tybulewicz and Lizzy Fisher
Rachael, we've just set up a collaboration to do the BrdU studies in developing brain.

Rachael Neve
But it would be in adult brain that BrdU incorporation would be interesting.

Lary Walker
Cell cycle, tau, phosphorylation…. It would be worth a look at Cdk5 and p25.

Victor Tybulewicz and Lizzy Fisher
Rachael, which cells are going into cell cycle? Could you give us more info regarding cell cycle entry and AD?

Rachael Neve
Sure; look up papers from Karl Herrup's lab and Inez Vincent's lab, for starters. (And see ARF related news story, ARF news story, recent live discussion on the relationship between cell cycle and DNA repair, and earlier live discussion on cell cycle reentry in AD).

Victor Tybulewicz and Lizzy Fisher
Thanks, John. Thanks, Rachael. Will have a think and a read….

Hunt Potter
Some, but not all, cell cycle markers in AD are in mice, too.

Victor Tybulewicz and Lizzy Fisher
Sorry, Hunt, do you mean in mouse models of AD?

Hunt Potter
 Yes.

Rachael Neve
Karl Herrup's lab made a real breakthrough when they identified tetraploid neurons in AD brain (see Yang et al., 2001). Tetraploidy is easier to look at in mice because you can do BrdU incorporation.

June Kinoshita
Oxidative stress is increased in Down syndrome brain, isn't it?

Victor Tybulewicz and Lizzy Fisher
Yes, oxidative stress is apparently increased in DS brain.

Jose Abisambra
Do you think heart malformation contributes to oxidative stress?

Victor Tybulewicz and Lizzy Fisher
Jose, absolutely no idea….

John Trojanowski
Another issue in DS is predilection to cancer, so is this also recapitulated in the DS mice?

Victor Tybulewicz and Lizzy Fisher
John, we have seen no cancer yet, but in fact, solid tumors are actually reduced in DS compared with the rest of the population, and there is an idea that there may (?) be a tumor suppressor on Hsa21.

John Trojanowski
Okay. I thought they got some type of leukemia or lymphoma. Any evidence of these in your model?

Hunt Potter
Right. There is only a specific leukemia that is more frequent in DS.

Rachael Neve
How about acute megakaryoblastic leukemia (AMKL), though, which occurs at a higher frequency in DS?

Victor Tybulewicz and Lizzy Fisher
Rachael, we have set up a collaboration to nosey further into the issue of AMKL. John, studies are ongoing. No evidence of leukemia at present.

Rachael Neve
You could start by looking at megakaryocytes for enlargement and proliferation in the bone marrow.

Victor Tybulewicz and Lizzy Fisher
Rachael, megakaryocytes are where we're heading currently.

Victor Tybulewicz and Lizzy Fisher
Regarding AMKL: We're introducing the mutated GATA1 into Tc1 mice to increase the chances of getting the disease.

William Mobley
Lizzy, Victor, greetings. I hope that I am not going over old territory here, having unfortunately missed most of the discussion, but are there plans to genetically mark the trisomic cells with green fluorescent protein (GFP) or some other fluorescently visible tag? In thinking through the studies in brain, it would be extremely important to be able to know with confidence which cells are trisomic.

Victor Tybulewicz and Lizzy Fisher
Bill, great suggestion, but hard to do, as we'd have to knock in a GFP construct to the Hsa21 and remake the mouse strain.

Rachael Neve
Bill, do you suspect that their mice may be chimeric?

Hunt Potter
Good point, Bill. Unfortunately, I must sign off now.

John Trojanowski
Victor and Lizzy, I must go now, too, but I have heard many productive suggestions for next steps related to investigating the DS-AD connection, so if I can be of further help, send me an e-mail. Best, John.

William Mobley
Victor and Lizzy should comment, but my reading of the paper suggests that only about 55 percent of brain cells retain the human chromosome.

Victor Tybulewicz and Lizzy Fisher
Bill, Hunt, regarding the mosaicism issue: Yes, absolutely right; only about 55 percent of brain cells carry Hsa21.

Jose Abisambra
I'll tell Hunt. Thank you.

June Kinoshita
What is the reason for the mosaicism?

Victor Tybulewicz and Lizzy Fisher
We don't know why Hsa21 is lost in a proportion of cells, but this accords with Oshimura's findings on mice he's made that carry portions of Hsa2, 14, and 22 (see, for example, Shinohara et al., 2004).

Rachael Neve
Is the mosaicism particularly prominent in brain?

Victor Tybulewicz and Lizzy Fisher
Rachael, no, not particularly compared to other tissues we've looked at. Probably all tissues are mosaic.

William Mobley
So, regarding the mosaicism issue, I think we really need to think how best to enable studies on the current mouse by using stains that identify the cells that contain Hsa21. Some studies are certainly doable at the single cell level, and the good news is that we will be able to ask about cell autonomous versus nonautonomous effects. So I am quite enthusiastic, but just need to strategize as to how best to proceed.

Victor Tybulewicz and Lizzy Fisher
Bill, agreed completely. What stains do you think might work? We've tried integrin β2 and one or two others without success.

Lary Walker
Regarding Bill's comments: How does mouse mosaicism compare to that in DS?

Victor Tybulewicz and Lizzy Fisher
A few patients (about 3 percent or less) are known to be mosaic in DS. Probably most of these studies come from blood, so who knows what's going on in the brain? From work, for example, of Jerold Chun at USCD, it does look as if there's aneuploidy in the normal human brain (see Rehen et al., 2001). We guess it might be difficult to get tissue in a good enough state to assay this, in humans.

Jose Abisambra
Have you noticed any vascular problems in the mice besides the heart?

Victor Tybulewicz and Lizzy Fisher
We haven't looked for specific vascular problems. What sort of thing would you expect?

Jose Abisambra
I am afraid that heart flow problems will further affect development, possible disease models (AD), etc., creating variables. I am particularly interested in possible atherosclerosis formation, but this should be down the road.

Victor Tybulewicz and Lizzy Fisher
Jose, interesting suggestion. Does this mean specific stains in older mice?

June Kinoshita
Jose, I've wondered whether there is an inhibition of angiogenesis in DS. Judah Folkman has speculated about this, because of the rarity of solid tumors in DS. I've wondered whether DS brain might be more poorly vascularized.

Lary Walker
There are also stereological methods for assessing degree of vascularization. Peter Mouton would know them well.

June Kinoshita
Regarding vascularization: Thomas Krucker at Novartis Research Institute in Cambridge, US, does beautiful polymer casts of microvasculature.

William Mobley
I need to give this some thought. But it would be good to brainstorm this together because you guys have been thinking about it for longer than I. Maybe June could set this up with others. A good solution would enable a good deal of research.

Victor Tybulewicz and Lizzy Fisher
Bill, agreed. June, cool idea. How would we follow up?

Jose Abisambra
Very good idea, June.

William Mobley
I have to go, but I just want to say how pleased I am that Lizzy and Victor have given us the opportunity to do so much more to study DS and AD. All the best!

June Kinoshita
In answer to Bill's suggestion, I'd be happy to set up another brainstorming session. We could also do this offline so people have time to compose longer comments.

Muriel Davisson
Lizzy and Victor, have you considered how you will distribute this model? If not—while everyone's still here—is this a model we should consider taking into the JAX cytogenetic models or AD repository?

June Kinoshita
Glad you raised that, Muriel! Regarding Jackson Labs: I was also thinking about a distribution colony, but Tc1 sounds like a challenging model to keep a colony going.

Muriel Davisson
I must sign off now, but let me know what the answers are to importing to JAX.

June Kinoshita
Thanks, Muriel!

Victor Tybulewicz and Lizzy Fisher
Muriel, we want to state explicitly that the mice will be available to anyone who wants them, but, we literally have no pairs of hands on this project at the moment, for the usual funding reasons, and our absolute priority is to get the strain frozen down. There is one small colony of these animals in the world, and if anything happens to them, that's it. After that, our next priority is to honor agreements with existing collaborators and get the mice to them. Then the mice will be freely available and we'll probably be quite glad to put them in a depository like JAX and/or the European equivalent, EMMA.

June Kinoshita
I'm afraid our hour is up, and I know Victor has to run off, but let's continue this discussion, by direct communication, by another forum discussion, etc. You're welcome to keep chatting. The room is open indefinitely.

Jose Abisambra
Thank you, all.

Lary Walker
Thanks, Lizzy and Victor, I look forward to seeing more on the mouse!

Victor Tybulewicz and Lizzy Fisher
June, thank you very much for organizing this, it's been tremendously helpful, and thank you to everyone who has contributed. We are definitely up for considering collaborations, as mentioned above. Best wishes to all.

Rachael Neve
I need to go; thank you, Victor and Lizzy, for sharing your thoughts with us!

June Kinoshita
Thanks Rachael!

Background

Because Down syndrome individuals almost invariably develop Alzheimer pathology and, in many cases, dementia, this mouse could provide a novel model system for elucidating mechanisms of AD pathogenesis. The authors report a loss of LTP in hippocampal neurons but so far no obvious AD pathologies such as plaques or hyperphosphorylated tau. Might there be subtler alterations in APP and its many offspring? An increase in ADDLs? Defects in axonal transport? Senior authors Lizzy Fisher and Victor Tybulewicz are eager to brainstorm online with interested Alzheimer scientists. Join them, along with Bill Mobley, John Trojanowski, Cindy Lemere, Dan Geschwind, Barbara Tate and others to ask questions, make suggestions and move forward the evaluation of this new mouse as a possible research model for AD. Or send your questions and comments by email to junekino@alzforum.org.

 

Reference
O'Doherty A, Ruf S, Mulligan C, Hildreth V, Errington ML, Cooke S, Sesay A, Modino S, Vanes L, Hernandez D, Linehan JM, Sharpe PT, Brandner S, Bliss TV, Henderson DJ, Nizetic D, Tybulewicz VL, Fisher EM. An aneuploid mouse strain carrying human chromosome 21 with down syndrome phenotypes. Science. 2005 Sep 23;309(5743):2033-7. Abstract

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References

Webinar Citations

  1. Could a New Down Syndrome Mouse Model Also Be Useful for Alzheimer Research?

News Citations

  1. Down's Syndrome Mouse Model Shows Facial Deformities
  2. AD Cell Cycle Reentry—Early Rather Than Late
  3. Linking APP with Cell Cycle Reentry and Apoptosis—One Kinase Does the Trick

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  1. . An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science. 2005 Sep 23;309(5743):2033-7. PubMed.
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  10. . Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13361-6. PubMed.

Other Citations

  1. junekino@alzforum.org

Further Reading

Papers

  1. . Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997 Mar 12;277(10):793-9. PubMed.