I think Brian Dickie must have planned the early morning slot of the International Symposium in Brussels as a talk that would make delegates sit up and take note. Southampton based Professor Hugh Perry’s presentation certainly made me do that on Sunday morning, the last day of the meeting.
His presentation was on the role of inflammation in neurodegenerative disease. ‘Most of what I’m going to talk about is not about MND’, he commented, ‘but I hope that it will have some resonance for you’. He started off talking about prion disease. In particular he is interested in cells that are called microglia that exist in the brain and spinal cord.
Perhaps about ten years ago the MND research world found out that it wasn’t just motor neurones we should be paying attention to in MND. There are cells called glial cells that support the function of motor neurones and come in all shapes and sizes in different parts of the brain. The whole set of talks in this session were dedicated to discussing their role in MND.
What, where and how?
Just like any good detective story (or news story) Professor Perry started with some basic questions – what do the microglia do in the brain of his mouse model (he was using prion disease as an example of neurodegenerative disease), where do the microglia come from and how do they contribute to neurodegeneration? He found the presence of more microglia in the brain of mice with neurodegenerative disease compared to unaffected mice. This higher number of microglia is also seen in the brains of people with prion disease and also in people with Alzheimer’s Disease.
Microglia and infection
From the time someone is born they are exposed to all manner of different infections – from colds to urinary infections. Depending on the nature of the infection explained Prof Perry, there will be short term (‘acute’) signs, eg fever and more long term (‘chronic’) signs of infection such as permanent tissue damage. ‘But what happens to microglia when someone with neurodegenerative disease gets an infection?’ asked Prof Perry, pulling together the two themes of his talk.
He showed a series of experiments tracking the body’s reaction to infection (sometimes described as inflammation) to the passage of these inflammation signals through the blood brain barrier (the brain’s protective covering) to interact with the microglia. As explained above, we know that the levels of microglia are already raised in neurodegenerative disease. Infection seems to exaggerate the damaging role of microglia – speeding up the loss of nerve cells. The chemical TNF alpha is well known in the medical field for being involved in inflammation. In the prion mouse the effects of microglia can be reduced by blocking TNF alpha. Crucially to MND research, the same chemical block, given to (the SOD1) mouse model of MND delayed onset of symptoms and slightly extended their survival. So its possible that a similar approach might help in people with MND.
My brother sister both had mumps an I didn’t an I slept in same bed as my sister ? My uncle I don’t no if he did but always wonder what sets it off I lost my uncle bk in 1986 age 54 my sister 44 2003 an my brother 2013 it so sad to see x
It seems that a lot of researchers are also wondering the same question. From your comment, it sounds like inherited MND may run in your family. If you would like further information on this rare form of MND please see our website: www.mndassociation.org/inheritedmnd or alternatively contact us on 01604 611 880 or firstname.lastname@example.org as there is a lot of research in this area, with a number of research opportunities to get involved in too?
on behalf of the Research Development team, MND Association, UK
There is a doctor here who has developed a pill that shuts down your DNA Casimir is his name Chris Carroll that works for the NSW MND Association told me about it. in fact I haven’t let up on her since but she won’t give me his surname. This would be good to do a trial with, he developed it for leukaemia and is not interested in MND. I think Chris would give the information if someone of interest could do it…..Paul I would be interested in being involved in the research on this..
Thank you for your comment. If you know the name of this pill we can investigate this further to find out if there is any science behind it? Please email email@example.com
on behalf of the Research Development team
Could this mean MND is in fact an auto immune disease?
I have read that roughly a third of MND cases have activated LSP/TLR4 and elevated IL-18 causing inflammation.
McGrath is presenting on NP001. See page 10 of the above pdf.
Discussion and conclusion: NP001 halted disease progres-sion in 27% of patients treated for 6 months, 2.5x the percent- age in the placebo group.
Two major plasma factors may differentiate NP001 responders from non-responders.
The responder population had signiﬁcantly higher levels of IL-18, a cytokine involved in inﬂammation driven cell death, than the non-responders.
Additionally, all NP001 responders had detectable LPS in their plasma, and LPS levels decreased in
most NP001 patients, consistent with normalization of macro-phage function and the mechanism of action of NP001.
Placebo patients without detectable LPS may represent a different slowly progressing population.
Importantly, elevated IL-18 and presence of LPS, markers indicative of an ongoing neuroinﬂ ammatory process, may help identify patients likely to beneﬁt from NP001.
Additionally, such markers may help identify different subpopulations in this heterogeneous disorder.
We found that upregulation of LPS/TLR4-signaling associated genes was observed in the PMBCs from sALS patients after short-term cultivation, and that elevated levels of gene expression correlated with degree of peripheral blood monocyte activation and plasma LPS levels in sALS.
Similar patterns of gene expression were reproduced in LPS stimulated PBMCs from healthy controls.
These data suggest that chronic monocyte/macrophage activation may be through LPS/TLR4-signaling pathways in ALS.
LPS/TLR4 signal transduction can be separated into MyD88-dependent and MyD88-independent pathways; the MyD88-dependent pathway was shown to be responsible for proinflammatory cytokine expression, while MyD88-independent pathway mediates the induction of type I interferons and interferon-inducible genes (Lu et al., 2008; Takeda and Akira, 2007; Tanimura et al., 2008).
Thus, sALS is characterized by evidence of systemic monocyte activation, in addition to local activation within disease affected spinal cords. This study shows for the first time a linkage between systemically activated monocyte/macrophages in sALS patients and the LPS/TLR4 signaling pathways.
Comments are closed.