One of the beauties of getting older without Alzheimers is that you still have a memory.
So a new study from the lab of Prof Franklinstein finds another new target to get repair.
Transforming growth factor-beta renders ageing microglia inhibitory to oligodendrocyte generation by CNS progenitors.Baror R, Neumann B, Segel M, Chalut KJ, Fancy SPJ, Schafer DP, Franklin RJM. Glia. 2019 Mar 12. doi: 10.1002/glia.23612. [Epub ahead of print]
It is now well-established that the macrophage and microglial response to CNS demyelination influences remyelination by removing myelin debris and secreting a variety of signaling molecules that influence the behaviour of oligodendrocyte progenitor cells (OPCs). Previous studies have shown that changes in microglia contribute to the age-related decline in the efficiency of remyelination. In this study, we show that microglia increase their expression of the proteoglycan NG2 with age, and that this is associated with an altered micro-niche generated by aged, but not young, microglia that can divert the differentiation OPCs from oligodendrocytes into astrocytes in vitro. We further show that these changes in ageing microglia are generated by exposure to high levels of TGFβ. Thus, our findings suggest that the rising levels of circulating TGFβ known to occur with ageing contribute to the age-related decline in remyelination by impairing the ability of microglia to promote oligodendrocyte differentiation from OPCs, and therefore could be a potential therapeutic target to promote remyelination.
In this study they say that transforming growth factor beta stops old macrophages from becoming young, which allows them to eat myelin rubbish and allow repair to occur.
The obvious approach is to fill someome full of transforming growth factor…….However, don’t do it.
Transforming growth factor is made as an inactive protein, because you do not want it active anywhere. You need it where it is needed. If can affect macrophages but it can also make cells called fibroblasts grow and.many other things.
In the past some not so quite so bright-sparks made the idea that there was a T helper cell that produced Transforming growth factor and was immunosuppressive.
In nature the active site is covered by a cap that is released in acidic environments (e.g. an inflammatory site).
So off we go trial…
However, they injected active protein and so it went every where and activated different things every where…End result
People with MS end up with severe kidney problems as the cytokine made fibroblasts in the kidney grow and formed a scar across the kidneys.
So a problem of running ahead and doing trials without thinking about biology and nature.
Now I am not suggesting that ProfF is actually going to do scarred kidney mark 2, although some not so bright spark neuro may read the paper and think there’s an idea.,…but the point I want to make here, is that essentially every molecule (these are factors produced inside cells) that has been found that promotes remyelination are used all over the body to do other things in different cell types.
Therefore long-term targeting myelin repair will most likely come with some side-effect so we have to decide do we need to use such treatments forever or ask if a pulse treatment can do the trock