Illustration of AB plaque build up on blood vessels.
Virginia Tech Carilion Research Institute scientists have uncovered a mechanism in the brain that could account for some of the neural degeneration and memory loss in people with Alzheimer’s disease. A buildup of misfolded proteins causes an exoskeleton (in blue) to form around blood vessels (in gold) in the brain. Credit: Virginia Tech.

New Understanding of Cause of Alzheimer’s Symptoms

Amyloid plaques may be strangling blood flow.

Virginia Tech Carilion Research Institute scientists have uncovered a mechanism in the brain that could account for some of the neural degeneration and memory loss in people with Alzheimer’s disease.

The researchers, together with scientists at the University of Alabama at Birmingham School of Medicine, discovered that a common symptom of Alzheimer’s disease – the accumulation of amyloid plaques along blood vessels – could be disrupting blood flow in the brain. The results were published Monday in the journal Brain.

“We’ve always been interested in how glial cells interact with blood vessels,” said Harald Sontheimer, director of the Center for Glial Biology in Health, Disease, and Cancer at the Virginia Tech Carilion Research Institute and senior author of the paper. “Astrocytes are the most populous cell type in the brain and even outnumber neurons.”

Sontheimer also noted the importance of astrocyte function in the brain.

“Astrocytes serve many support functions, such as shuttling nutrients from blood vessels to nerve cells or removing their waste products,” said Sontheimer, who is also the I. D. Wilson Chair in Virginia Tech’s College of Science. “They also control the diameter of blood vessels to assure proper nutrient and oxygen delivery to the brain and maintenance of the blood-brain barrier. In response to injury and disease, however, astrocytes become reactive and change many of their supportive properties.”

Sontheimer’s team discovered that the astrocytes’ blood flow regulation is disrupted by plaques formed of misfolded amyloid protein around blood vessels. In a healthy brain, amyloid protein fragments are routinely broken down and eliminated.

The presence of amyloid proteins around blood vessels in the brain is a hallmark of Alzheimer’s disease, yet it wasn’t understood if the proteins did any harm. Now, Sontheimer’s team has found that they do.

“We found that amyloid deposits separated astrocytes from the blood vessel wall,” said Stefanie Robel, a research assistant professor at the Virginia Tech Carilion Research Institute and a coauthor of the paper. “We also found that these amyloid deposits form an exoskeleton around the blood vessels, a kind of cast that reduces the pliability of the vessels.”

The exoskeleton is known as a vascular amyloid. Its inelasticity might result in lower blood flow, which could account for Alzheimer’s symptoms, such as memory lapses, impaired decision-making, and personality changes.

Illustration of AB plaque build up on blood vessels.
Virginia Tech Carilion Research Institute scientists have uncovered a mechanism in the brain that could account for some of the neural degeneration and memory loss in people with Alzheimer’s disease. A buildup of misfolded proteins causes an exoskeleton (in blue) to form around blood vessels (in gold) in the brain. Credit: Virginia Tech.

“Vascular amyloid may be the culprit in Alzheimer’s disease symptoms, especially considering that the amyloid exoskeleton might limit the supply of oxygen and glucose to the brain regions that need them most,” Sontheimer said. “This could also explain the cognitive decline in people with Alzheimer’s disease, as the disease is associated with reduced cerebral blood flow.”

While the scientists don’t fully understand the role of vascular amyloid in Alzheimer’s disease, they now have a possible therapeutic target to study.

“It may be helpful to remove the deposits to allow for appropriate blood flow,” Robel said. “The problem is we don’t know. It might be harmful to remove vascular amyloid at late stages of the disease; maybe they’re actually holding the vessels together.”

The researchers’ next step will be to examine blood vessels once the amyloid deposits are removed.

“Vascular amyloid is strangling the blood vessels,” Sontheimer said. “By removing them, maybe we’ll be able to restore blood flow regulation. Perhaps it’ll turn out vascular amyloid is preventing further degeneration. Whatever the case, we’ll certainly learn something new.”

About this neurology research

Funding:

Source: Paula Byron – Virginia Tech
Image Source: The image is credited to Virginia Tech
Original Research: Abstract for “Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease” by Ian F. Kimbrough, Stefanie Robel, Erik D. Roberson, and Harald Sontheimer in Brain. Published online November 23 2015 doi:10.1093/brain/awv327


Abstract

Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease

Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer’s disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer’s disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca2+ uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer’s disease.

“Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease” by Ian F. Kimbrough, Stefanie Robel, Erik D. Roberson, and Harald Sontheimer in Brain. Published online November 23 2015 doi:10.1093/brain/awv327

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