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Microglia Stem Cells: Questions to the researchers

project microglia stem cells

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#1 caliban

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Posted 11 November 2010 - 07:42 PM


We are looking to fund projects where the researchers are available and accountable to the donor community.

Mondey and her graduate student Arndt are both ImmInst members and will be available to answer questions and consider suggestions and ideas.

As usual, please bear in mind that the first thing we want these researchers to do is to focus on life-extension research, so please give them some time to answer.

Edited by caliban, 12 January 2012 - 11:36 PM.


#2 ArndHinze

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Posted 12 November 2010 - 04:28 PM

I'm Arnd. If you have any questions about the project, criticism, problems with the outline, suggestions, flames feel free to post.

bye,

Arnd


P.s.: I just have to add that I do not have a computer at home. If the reply takes a bit time please don't be upset.

Edited by ArndHinze, 12 November 2010 - 04:29 PM.

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#3 Mondey

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Posted 13 November 2010 - 02:28 PM

Hi everybody,
I will be delighted to answer questions and consider your suggestions. In the first round we already got some nice and interesting references send which were related to the project. So keep posting all material available that will be related to the project. Your help is very much appreciated.
Greetings,
Dey
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#4 brokenportal

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Posted 03 December 2010 - 06:17 PM

Could you give us a brief summary of what other related kinds of microglial projects have produced in the past?
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#5 ArndHinze

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Posted 04 December 2010 - 01:21 PM

Could you give us a brief summary of what other related kinds of microglial projects have produced in the past?


Mondey has done *much* more than me. I screened microglia differentiation and proved function of such in vitro differentiated microglia. I also transplanted MSC and non adherent bone marrow cells to investigate a possible regulation of inflammation etc. of microglia in age. I'm just writing that down in papers and PhD thesis.
Mondey did a lot about microglia becoming dysfunctional in age, but much more. She can probably tell you best herself.
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#6 Mondey

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Posted 11 December 2010 - 07:33 PM

Dear Brokenportal,
they have been only three projects that I am aware of in relation to microglia. Two are from this year (February and July). They have transplanted a human microglia cell line into rats with stroke. They showed improvements in relation to infarct size and behavior. This study would support our project and give us hope that we might also find beneficial effects.

Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement. Narantuya D, Nagai A, Sheikh AM, Masuda J, Kobayashi S, Yamaguchi S, Kim SU. PLoS One. 2010 Jul 23;5(7):e117
46.

The difference between the stroke model and our Alzheimer model (and even more important our normal aged controls) is that we deal with chronic damage. It might be that the microglia will function differently maybe not.

The second study is on a chronic model (again ischemia) using the same cell line and is also from the same group. Again they find some benefits (reduced white matter lesion).

Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition. Narantuya D, Nagai A, Sheikh AM, Wakabayashi K, Shiota Y, Watanabe T, Masuda J, Kobayashi S, Kim SU, Yamaguchi S. Brain Res. 2010 Feb 26;1316
:145-52.

Again the damage is local and from a different kind then we find in Alzheimer or aging.

A third study was performed on activated microglia in a rat spinal cord model (Yu et al., 2009) and they show functional improvement.

Some other related studies are on bone marrow transplantations (you can also find them in our proposal text).

In total I think there is enough positive results to be found in the internet to support our theory. But to be sure we simple have to test it. So I am very glad for every penny going into our research and I truly believe that we will find out something: either that it works and we find improvements or if not then we will have found new information for the role of the microglia in Alzheimer/aging and that will help us to generate new models for therapies.

Greetings,
Dey
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#7 brokenportal

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Posted 04 January 2011 - 11:25 PM

If you support this research then you can help make it happen by Donating here:

http://www.imminst.org/forum/index.php?app=donate'> src='http://www.paypal.com/en_US/i/btn/btn_donate_LG.gif' alt='donate_button' />

Posted Image

http://www.imminst.org/forum/index.php?app=donate'> src='http://www.paypal.com/en_US/i/btn/btn_donate_LG.gif' alt='donate_button' />

You can read about it in the front page article.

Edited by brokenportal, 01 June 2011 - 04:03 AM.


#8 The Immortalist

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Posted 09 January 2011 - 09:57 PM

Hi everybody,
I will be delighted to answer questions and consider your suggestions. In the first round we already got some nice and interesting references send which were related to the project. So keep posting all material available that will be related to the project. Your help is very much appreciated.
Greetings,
Dey


I was wondering if there could be a video interviewing the stem cell biology unit about the project. Is it just you and Arnd who are doing the project or is it the entire unit? If anyone takes the initiative to make this video could you include some footage of the actual research being done to the mice and the instruments you use?
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#9 Mondey

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Posted 13 January 2011 - 12:20 PM

Hi,
in principal this would be possible. There are however some hurdles. I do not have a video camera. If you know somebody with some experience and is living near the lab, then we can organise a tour through the lab and some interviews with the people working here.
Not everybody of the group is working on this project but I do want to increase the number of people involved in this area. The other projects we have are human non viral iPS cell generation and MSC modification.
Greetings,
Dey
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#10 Mondey

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Posted 27 January 2011 - 02:22 PM

Hi everybody,

I wanted to thank all of you for the support and the donations. You do not know how nice and exiting this is for me. Usually you write such a project and you send it some funding agency and you never here from them any more until you either get your paper saying you get funding or the sometimes were nasty letters saying you do not get funding because measuring how much fat a diabetic pekingese is so much more exiting.

Your donations and your messages saying you like to project gives me a lot of motivation and I like to hear from every one of you what you like about it or not and I am happy about all the comments I get from you.

So thanks already for your trust and support.

Greetings,

Mond
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#11 Pour_la_Science

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Posted 09 February 2011 - 08:25 PM

Hi! I'm reacting a bit in relation with the Newsletter (it's good to have that to be informed, continue that!).
I was discussing with somebody about the aging-related diseases and the question about Alzheimer. My point was that I think that Alzheimer IS a disease directly connected with aging. If you are "lucky" enough to become old, everybody would get Alzheimer!
That was my point, more based about the evolution of the incidence of the disease (It keeps on growing with age) and some intuition too, but not scientific studies on physiopathology or molecular studies.

In the Newsletter, we can read this extract :

Bad news: You have Alzheimer's! Sorry to tell you, but your brain is aging! While genetic dispositions differ, if you don't die of other causes, neurodegeneration will eat away your intelligence and personally eventually, and we know now that the process is likely already underway. This was shown, years ago, not least by the team we are trying to support with the still ongoing Microglia Stem Cells project!



My opponent in discussion was arguing that it's only a particular type of persons who gets the disease (even if it's a very big number of people), and so this make Alzheimer completely different from a "normal"aging.
I would be very happy to get more info if you have more about this theory suggested in this Newsletter, especially for my personal "work" in convincing more people with the right argument !

Edited by Pour_la_Science, 09 February 2011 - 08:26 PM.


#12 caliban

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Posted 21 February 2011 - 12:41 AM

Hey Pour_la_Science,

I leave the researchers to answer more if they like, but they shouldn't have to defend what caliban writes in a newsletter to drum up more donations. :sleep: So very superficially:

My words were chosen for dramatic effect. Still, I stand by them for the following reasons: The question of what 'Alzheimners' entails is still not settled. Early onset Alzheimer's disease is generally autosomal dominant but genetically heterogeneous. However, what we find in the genetic conditions is simply a flaw in the management of that mean those afflicted get the affected by protein debris faster. Other forms of Alzheimer's are not genetically linked and its jolly difficult to diagnose Alzheimers while people are still alive: decreased amyloid-b peptides and increased tau concentration in CSF are generally taken as a sign of Alzheimers, but there is no clear link with psychological/cognitive impairment! For a while, we thought, that there may be some Alzheimers-protection in the oldest old, but event that assumption has now been questioned (1)/(2).
However, does it really matter? Old people get dementia! Does it matter if its from Alzheiners or LBD or some other factor related to proteolysis going wrong? Sometimes researchers working with the oldest old are so impressed by them that they make statements to the contrary, but wherever I have challenged people on this point, they had to agree that there was some apparent cognitive decline in these methuselahs. Mondeys research has found that microglia - the cells they are trying to refresh - become less efficient in 'eating' up protein in middle age (3) and that proteasomal activity is impaired in Alzheimers (4). Sure, there will be individual differences in how long that deterioration takes based on genes, lifestyle and luck, but there is no reason to assume that this steady deterioration will not happen in some individuals. This is only one aspect of what goes wrong in the brain that causes neurodeneneration, but its the aspect under review here.
On the bright side: if (big if!) this therapy succeeds it will be effective in all kinds on protein-debris associated neuropathology. Because the miki cells don't care why the junk is there, their job is to clear it.

For that reason, if you read the whole item, you will see that I avoid using the word Alzheimers again. What is and what isn't Alzheimers is a matter of definition, still being argued over in the field. I challenge anyone to disprove that proteolysis-associated inflammatory neurodegeneration (PAIN? -Maybe one just needs a better acronym that is as short as Alzheiners?) will not lead to dementia in all of us eventually.



Refs:
(1) U. Lucca, M. Garri, A. Nobili, et al., “Risk of dementia continues to rise in the oldest old: the Monzino 80-plus study,” Alzheimer's & Dementia, vol. 5, no. 4, supplement, p. 381, 2009.
(2) M. M. Corrada, R. Brookmeyer, D. Berlau, A. Paganini-Hill, and C. H. Kawas, “Prevalence of dementia after age 90: results from the 90+ study,” Neurology, vol. 71, no. 5, pp. 337–343, 2008.
(3) Stolzing et al "Chronically active: Activation of microglial proteolysis in ageing and neurodegeneration" Redox Report Volume 10, Issue 4, August 2005, pp.207-213
(4) Mishto et al "Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains"
Neurobiology of Aging Volume 27, Issue 1, January 2006, pp 54-66

#13 KrusherX

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Posted 16 March 2011 - 03:29 PM

Considering the numerous results by Rivest's, Gordon's and El Khoury's teams on the effectiveness of bone marrow transplantation for the treatment of AD, what exactly will this project bring that is new?
Also, with the absence of a pretreatment, how will you circumvent graft vs host rejections?
Outside of the CNS, how can you differentiate between microglias and macrophages?
Why use sex differenciation rather than GFP+ cells for the tracking of grafted cells?
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#14 Hip

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Posted 30 April 2011 - 06:22 AM

I understand that microglia are regularly replaced all the time, by new microglia made from stems cells.

Microglia cells are made in a person's bone marrow, from the hematopoietic stem cells in the marrow, and then these microglia migrate to the brain. (Though existing microglial cell can also replicate via mitosis in the brain, and so this mitosis is another source of new microglial cells).

Edited by Hip, 30 April 2011 - 06:27 AM.


#15 brokenportal

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Posted 19 May 2011 - 01:01 AM

Being that microglial cells derive themselves from bone marrow stem cells, I wonder if embryonic stem cells would even have an advantage in this case.


This fundraiser is almost there everybody, thanks to your help, just a little further. Any body with a few dollars please do consider donating and helping to chalk this up as another community success. (this would arguably be the biggest one so far)

#16 Mondey

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Posted 22 June 2011 - 05:07 PM

Dear Pour_la_Science
Most theories, and there are all still theories, claim that the incidence to get Alzheimer increases with age. There are risk factors associated with Alzheimer and these persons are more likely to get Alzheimer. There seems also be the opposite the super-centenarians which might be less likely to get Alzheimer.
As long as we do not fully understand Alzheimer we can not say how similar it is to normal aging or not.
But also this is included in my study as I have included one group of “normal” age-matched mice which also gets cells transplanted. So in the end we will hopefully see if there is a difference between these groups or not. But even then we have to be careful as mice are an artificial Alzheimer model with just some features of “normal” human Alzheimer.
In the moment I think that Alzheimer is identical to normal brain aging.

Greetings,
Dey

#17 Mondey

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Posted 22 June 2011 - 05:27 PM

Dear KrusherX
1) I am transplanting microglia not bone marrow. I think microglia are more effective and prefere to have them as pure cell pouplulation. Sure in bone marrow contain macrophages as well, but they are less frequent. We have nearly 80-90% pure microglia populations.
2) I already did some preliminary transplantations and did not observe any graft versus host rejections and non of our mice died. I am particularly interested in the role of the microglia and their role in brain aging.
3) There is a big debate about the difference between microglia and macrophages and if there is a difference or not. I do not want to ponder if the difference exist or not. I define microglia as CD11b high expression and CD45 median expression in comparison to macrophages which were described to be CD45 and CD11b high (Ford et al., 1995).
4) We used sex mismatch because GFP induces an oxidative stres in cells and I did prefere a completly unchanged cell. In addition GFP can sometimes become silenced with time and the signal would be lost. These were my reasons to go for sex-mismatch over GFP-mice, but they could be used as well. Do you have any experience with both techniques in comparison ?

Greetings,
Dey

Edited by Mondey, 22 June 2011 - 05:39 PM.






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