Alzheimer's: the promising lead in removing tau protein deposits

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Alzheimer : the promising lead in the elimination of tau protein deposits

Phosphorylation (yellow) of tau protein (red-orange) results in the disintegration of microtubules and aggregation into neurofibrillary tangles (orange) in the axon of a neuron.

Certain diseases characterized by abnormal deposits of tau protein could one day be a thing of the past thanks to the work of a Montreal researcher and his team.

< p class="e-p">These diseases, perhaps the best known of which are Alzheimer's disease and glaucoma, are collectively known as tauopathies. They have in common an abnormal intracellular accumulation of the tau protein, to the point where it becomes toxic for the neurons and leads to their degeneration.

Doctor Michel Cayouette, from the The Montreal Clinical Research Institute (IRCM), however, and his colleagues have discovered that it is possible not only to remove these deposits, but also to reverse the symptoms they cause by influencing blood levels. #x27;a protein called Numb.

Researchers first found that inactivating Numb in retinal neurons and motor neurons in the spinal cord accelerated disease progression and neuron loss, putting them on the discovery trail announced Thursday.

We wondered if we could do the opposite, said Dr. Cayouette. Could we find a way to increase levels of this Numb protein in cells? And could it become a therapeutic tool?

Researchers' attention was quickly drawn to a very specific form of the Numb protein, Numb-72. When this protein was overexpressed and introduced into diseased neuronal cells, a dramatic decrease in tau levels was observed.

< p>“It becomes a therapeutic tool because you can target tau levels and reduce them simply by introducing a very specific form of the Numb protein into neuronal cells. »

— Michel Cayouette, doctor at the Montreal Clinical Research Institute

What's more, when the researchers treated diseased mice towards the end of their study, they found not only a slowing of the progression of the disease, namely that the neurons of the retina died less quickly than in mice treated with a placebo, but also that the critters' vision improved – in other words, the symptoms of the disease lessened.

This improvement, said Dr. Cayouette, most likely occurs because tau levels in neurons have been brought down to functional levels.

It's super exciting, because it seems that by introducing this Numb-72 protein into the cells, we manage to improve neuronal function, enthused the researcher.

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“Even if we catch the cells at a time when we have lost a certain number of them, we can save the neurons that remain. And not only save them, but make them even more functional and therefore improve their ability to respond and mediate vision in this case. »

— Michel Cayouette, doctor at the Clinical Research Institute of Montreal

And since Numb-72 seems very specifically dedicated to the regulation of tau, the researchers have not yet detected any adverse side effects resulting from its overexpression. Several other studies will however be necessary in order to validate their conclusions, in particular on human neurons and in other animal models.

They envisage the possible development, in several years, of #x27;a drug that would be a truncated form of Numb-72, so as to retain only the really essential parts of the protein to fight tau deposits.

That's almost 20 years now that I have a research group here at the IRCM, then I would say that it is probably the discovery that is closest to a possible application in the human, concluded Dr. Cayouette.

The findings of this study were published in the journal Science Advances.

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