White Blood Cells Degrade Capillary Blood Flow to Contribute to Age-Related Neurodegeneration

Researchers here outline a new discovery regarding the origin of reduced blood flow in the aging brain; white blood cells are clogging up capillaries. It is well known that the supply of blood is reduced in tissues with age; this is studied in muscles and the brain, among other tissue types. Some researchers blame a reduction in capillary density in later life, others consider reduced capacity of the heart to pump blood uphill to the brain. A lesser flow of blood in any specific tissue will affect its function, especially in energy-hungry tissues such as the brain, as the supply of oxygen and nutrients is reduced.

In the case of the results reported here, I have to wonder whether this might tie in some way to the observed reduction in capillary density with age; does blockage by white blood cells result in significant capillary atrophy at the smallest scale of blood vessels? There are certainly other mechanisms by which that outcome could occur, and this may not be an important contribution even it does produce atrophy to some degree.

The existence of cerebral blood flow reduction in Alzheimer's patients has been known for decades, but the exact correlation to impaired cognitive function is less understood. "People probably adapt to the decreased blood flow, so that they don't feel dizzy all of the time, but there's clear evidence that it impacts cognitive function." A new study offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.

The work began with a study in which researchers were attempting to put clots into the vasculatures of Alzheimer's mouse brains to see their effect. "It turns out that the blockages we were trying to induce were already in there. It sort of turned the research around - this is a phenomenon that was already happening." The researchers determined that only about 2 percent of brain capillaries had "stalls" (blockages), but the cumulative effect of that small number of stalls was an approximately 20 percent overall decrease in brain blood flow, due to the slowing of downstream vessels by the capillaries that were stalled.

Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia. To test the effect of the stalls on performance of memory tasks in Alzheimer's mice, they were given an antibody that interfered with the adhesion of white blood cells to capillary walls, which caused the stalled capillaries to start flowing again and thus increased overall brain blood flow. Memory function was improved within a few hours, even in aged mice with more advanced stages of Alzheimer's disease.

Link: http://news.cornell.edu/stories/2019/02/brain-blood-flow-finding-gives-hope-alzheimers-therapy


Thanks for this Reason. This is all in mice right. No human testing. Just wondering. Also, does the paper say -why- the wbcells begin to adhere?


Posted by: David Gobel at February 18th, 2019 8:53 AM

@David Gobel: Yes, all in mice. In the discussion section of the paper, the researchers note the belief that this increased adherence is secondary to chronic inflammation:

"Inflammation is a persistent and well-recognized feature of Alzheimer's disease, and previous work has demonstrated an increase in inflammatory adhesion receptors on endothelial cells, which probably underlies the capillary stalling we observed. A major contributor to this inflammation is increased reactive oxygen species induced by brain exposure to Aβ oligomeric aggregates. These reactive oxygen species cause a loss of cerebrovascular flow regulation and probably drive the expression of leukocyte-binding receptors on the endothelial cell surface, such as ICAM1 and VCAM1. Our observation that certain capillary segments were more likely to stall suggests that the underlying vascular inflammation may not be uniform."

Posted by: Reason at February 18th, 2019 9:05 AM

Thanks Reason. So, the oligomeric aggregates which are not cleared hang around and do damage and cause even more white blood cells to hang around and do further damage downstream. Do I have that right?

Posted by: Dave Gobel at February 18th, 2019 11:36 AM

@David Gobel: I don't think there's consensus on the hierarchy of contribution sizes for the causes of neuroinflammation. Senolytic studies strongly suggest that senescent microglia are a big cause, for example, and it is hard to place their senescence 100% at the foot of aggregates. Other work strongly suggests breakdown of the blood-brain barrier to be a big cause. Other work suggests persistent infection. Too many processes feeding back into one another.

Posted by: Reason at February 18th, 2019 11:49 AM

I wonder if white blood cells getting stuck in capillaries causes disease in other parts of the body, or in the lymphatic system? Also why is it as slow a process as it is? Why don't inflammatory periods cause capillary loss in tissues in the young?

Posted by: jimofoz at February 18th, 2019 12:10 PM

Note that low white blood cell count (WBC) is a well known hallmark of calorie restriction and to a lesser extent of even just vegan diets, and whether or not the low WBC is a net healthy thing or a cause of concern is a frequently discussed topic in communities of both those 2 eating styles. Those who think the low WBC is good typically think so because they see it primarily as a marker of low chronic inflammation. This is an interesting new angle.

Posted by: Karl Pfleger at February 19th, 2019 11:02 PM

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