Stroke is a major cause of death and disability, and there is only a short window for therapeutic intervention, aimed at restoring blood flow to the brain before neurons are irreversibly damaged.
The study published in Nature Communications finds that mice deficient in tau, a protein within brain cells (neurons), are significantly protected from excitotoxic brain damage after experimental stroke.
"Tau as a drug target is intensively explored in Alzheimer's disease, but as a drug target in stroke is completely new thinking," senior author says.
"That's where our paper has implications beyond mouse model molecular work. Drug development in this space should consider stroke as a disease that you can treat by targeting tau," another author added.
They demonstrate profound protection from brain damage, of more than 90 per cent, in the absence of tau. Authors show that the protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau−/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage.
Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. These findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.
The authors caution that these findings were made in mouse models only, and that pathways to therapies take decades.
https://newsroom.unsw.edu.au/news/health/study-offers-new-mindset-search-stroke-therapies
https://www.nature.com/articles/s41467-017-00618-0
Tau's role in stroke!
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