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New clot-clearing mechanism has implications for many big diseases

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Posted on behalf of Alison Abbott

Some papers that one might imagine would fire a storm of interest fail at first to resonate in the scientific community. This was the case with neurologist Jaime Grutzendler’s Nature paper published last May. He described an entirely new and surprising biological mechanism, whereby the tiniest capillaries in the brain clear themselves of micro-blood-clots as well as other junk in the blood, such as fragments of cholesterol plaques or cellular debris.

He and his team, then at Northwestern University in Chicago, used advanced microscopic techniques to show that the clots extend the capillary’s endothelial membrane around themselves. The capillary then opens a gap in its walls through which the clot is ushered out. At the same time, the membrane surrounding it seals a new wall across the gap. In this way, the capillary avoids creating a hole through which blood could leak and cause local brain damage. Grutzendler calls this mechanism angiophagy.

The team showed that this mechanism gets less efficient with age.

Grutzendler, who is now at Yale University in New Haven, Connecticut, presented an extension of this work at the annual meeting of the Society for Neuroscience in Washington DC today (15 November). He described how this mechanism operates throughout the body, not just in the brain as he had originally assumed.

The discovery has implications for many diseases, such as stroke, which is caused by blood clots blocking normal-sized blood vessels in the brain. Treatment with clot-busting enzymes such as tissue plasminogen activator (tPA) fling tiny fragments into the blood stream, where they can end up getting stuck in the micro-vessels. An inefficient angiophagy system would not be able to handle this — potentially explaining why tPA therapy sometimes fails to prevent brain injury.

It also has implications for dementias. Dementias occur as a consequence of vascular damage, or (in the case of classical Alzheimer’s) amyloid-plaque pathology, or both. Many people suffer frequent, tiny strokes that pass unnoticed because they cause no symptoms. Inefficient angiophagy may accelerate the slow accumulation of damage around tiny blocked capillaries to destructive levels. In Alzheimer’s, amyloid peptides can also deposit in blood vessels as well as around neurons — thus adding vascular damage to plaque damage if capillaries cannot clear them efficiently.

Grutzendler’s latest results indicate that some peripheral diseases may also be worsened by inefficient angiophagy, as with the temporary blindness that can occur when retinal blood vessels are blocked. Recovery from heart attack might also be affected, he says.

“I think the pick-up on the paper was slow at first because it fell between interest areas — we didn’t actually key-word things like ‘Alzheimer’s’”. But now invitations to speak at specialist meetings are starting to trickle in, he says.

He is now trying to dissect out the molecular components of angiophagy with the hope of identifying drug targets.

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