Decline in the Supporting Cells of the Blood-Brain Barrier Precedes Dementia

The brain is locked away from the biochemistry of the rest of the body behind the blood-brain barrier, the sheath of specialized cells surrounding blood vessels in the brain that prevents most unwanted molecular traffic to and from neural tissues. The brain is biochemically quite different from the rest of the body, and many of the commonplace molecules found elsewhere can be harmful to brain tissue or degrade neural function. Pericytes are one of the supporting cell types involved in the structure of the blood-brain barrier, and in the research noted here, pericyte dysfunction is linked to other known aspects of biochemical disarray in the vascular system that take place with aging. These include: the leakage of fibrinogen into the brain and its damaging effects on nerves; the progressive failure of blood-brain barrier integrity, allowing other forms of leakage; the buildup of protein aggregates that harm neurons; and the general vascular dysfunction that impacts the delivery of nutrients to the energy-hungry brain.

What can be done about this? The research here identifies the functional failure of pericytes as the earliest cause in the stack of consequences that the authors examined, but they look at managing fibrinogen as the first option for therapies. This is a sadly common sort of approach, meaning to work on the manipulation of consequences rather than addressing lower causes. To my eyes, the better way forward would be to dig deeper into the dysfunction of the cells of the blood-brain barrier, to ask why they are declining. There is a rich literature of investigation regarding blood vessel dysfunction, one that is starting to touch on the contributions of the root causes of aging, such as cellular senescence. More could certainly be done in that direction, rather than immediately preparing the ground for attempts at clinical translation of what has been learned so far.

Half of all dementias, including Alzheimer's, start with damaged 'gatekeeper cells'

Nearly 50 percent of all dementias, including Alzheimer's, begins with the breakdown of the smallest blood vessels in the brain and their protective "gatekeeper cells," according to a new study. That catastrophe causes a communications failure called small vessel disease. Many people with that disease also have white matter disease, the wearing away of fatty myelin that allows neurons to transfer messages within the brain network. In an animal model, researchers found that brain deterioration associated with dementia may start as early 40 in humans.

For more than 25 years, scientists have known that white matter disease impedes a person's ability to learn or remember new things, slows thinking and causes people to fall more often due to balance issues. They identified a link between crippled small blood vessels in the brain and white matter disease but didn't know what started that process until now. "Many scientists have focused their Alzheimer's disease research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier - with leaky blood vessels in the brain. The collapse of pericytes - gatekeeper cells that surround the brain's smallest blood vessels - reduces myelin and white matter structure in the brain. Vascular dysfunctions, including blood flow reduction and blood-brain barrier breakdown, kick off white matter disease."

The study explains that pericytes play a critical role in white matter health and disease via fibrinogen, a protein that circulates in blood. Fibrinogen develops blood clots so wounds can heal. When gatekeeper cells are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures, including axons (nerve fibers) and oligodendrocytes (cells that produce myelin), to die. The researchers are the first to show that fibrinogen is a key player in non-immune white matter degeneration. The protein enters the brain through a leaky blood-brain barrier. The study found about 50 percent fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas in postmortem Alzheimer's brains of humans compared to healthy brains.

To confirm that fibrinogen proteins are toxic to the brain, researchers used an enzyme known to reduce fibrinogen in the blood and brain of mice. White matter volume in mice returned to 90 percent of their normal state, and white matter connections were back to 80 percent productivity. "Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease. It provides a target for treatment, but more research is needed. We must figure out the right approach. Perhaps focusing on strengthening the blood-brain barrier integrity may be an answer because you can't eliminate fibrinogen from blood in humans. This protein is necessary in the blood. It just happens to be toxic to the brain."

Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons, and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs.

Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.

Comments

" To my eyes, the better way forward would be to dig deeper into the dysfunction of the cells of the blood-brain barrier, to ask why they are declining. There is a rich literature of investigation regarding blood vessel dysfunction, one that is starting to touch on the contributions of the root causes of aging, such as cellular senescence. More could certainly be done in that direction, rather than immediately preparing the ground for attempts at clinical translation of what has been learned so far."

Thanks for this blog post Reason. I read through the USC Press Release and paper and was also wondering why the authors didn't suggest going after the causes of the decline in support cells rather than the consequences (buildup of fibrinogen and other gunk, perhaps amyloid beta).

On the other hand, if removal of senescent cells could be shown to slow or stop the decline in Pericytes and have a potential impact on Alzheimers, there might be an uptick in investor interest in companies like Unity/Oisin. Pericytes could prove to be a new biomarker in Alzhiemers for these senescent cell removal companies to aim at, and a much cheaper and faster biomarker than just trying to measure cognitive function in large groups of seniors with Alzheimers.

Posted by: Jim at February 7th, 2018 12:36 AM

"To my eyes, the better way forward would be to dig deeper into the dysfunction of the cells of the blood-brain barrier, to ask why they are declining."

But the researchers have straight out said that the better target than fibrinogen is improving the integrity of the BBB.

"Perhaps focusing on strengthening the blood-brain barrier integrity may be an answer because you can't eliminate fibrinogen from blood in humans. This protein is necessary in the blood. It just happens to be toxic to the brain."

That would imply they will investigate why the BBB fails and that road leads to targeting the cause of that failure. They are not talking about targeting fibrinogen because that is not an option.

Posted by: Steve Hill at February 7th, 2018 8:25 AM

"Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease. It provides a target for treatment, but more research is needed. We must figure out the right approach."

And yes they said this too but they absolutely realize that you cannot blockade fibrinogen systemically because it's critical elsewhere in the body. Investigating BBB integrity makes sense and this is the direction they appear to be heading.

Posted by: Steve Hill at February 7th, 2018 8:27 AM

In the last couple days we are seeing more studies showing that aging is the disease and all these other 'diseases' are merely symptoms. Hmm.. Wonder where I heard that before.....

How long before the medical community FINALLY arrives at the same conclusion?

Posted by: Mark Borbely at February 7th, 2018 9:46 AM

Its already happening Mark

Posted by: Steve Hill at February 7th, 2018 10:13 AM

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