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Blood Flow in Brain Takes a Twist, Affecting Views of Alzheimer's

Are astrocytes gone wild starving neurons from oxygen

Jan. 6,2006 - New findings that long-overlooked brain cells play an important role in regulating blood flow in the brain call into question one of the basic assumptions underlying today's most sophisticated brain imaging techniques and could open a new frontier when it comes to understanding Alzheimer's disease.

In a paper to appear in the February issue of Nature Neuroscience and now available on-line, scientists at the University of Rochester Medical Center demonstrate that star-shaped brain cells known as astrocytes play a direct role in controlling blood flow in the brain, a crucial process that allows parts of the brain to burst into activity when needed.

The finding is intriguing for a disease like Alzheimer's, which has long been considered a disease of brain cells known as neurons, and certainly not astrocytes.

"For many years, astrocytes have been considered mainly as housekeeping cells that help nourish and maintain a healthy environment for neurons. But it's turning out that astrocytes may play a central role in many human diseases," said neuroscientist Maiken Nedergaard, M.D., Ph.D., who has produced a string of publications fingering astrocytes in diseases like epilepsy and spinal cord injury.

"In a disease like Alzheimer's, for instance, perhaps it's the astrocytes themselves that are damaged first," she said. "It may be that for whatever reason, astrocytes are not doing their job properly, and then blood flow decreases. This could lead to the death of the neurons, which would starve from a lack of nutrients, since the neurons depend on the astrocytes for their survival."

The new research focuses on a process critical to the health of people with Alzheimer's and everyone else: the moment-to-moment allocation of vital resources like oxygen that goes on within our bodies.

It's a supply problem familiar to anyone who worried over the availability of gasoline immediately after hurricane Katrina. In our bodies the process is particularly crucial in the brain, which is the body's most voracious guzzler of "fuel," with a constant need for oxygen. When part of the brain becomes more active, more blood is shunted to that region to bring extra nutrients like oxygen, making the increased activity possible.

Most scientists have assumed that the more blood that flows to a particular part of the brain, the more activity on the part of neurons, the nerve cells that send electrical signals that are widely considered to be "brain activity."

The assumption that more blood flow equals more active neurons forms the basis for interpretation of sophisticated brain imaging techniques such as PET scans and functional MRI scans.

Now the group led by Nedergaard, professor in the Department of Neurosurgery and a member of the Center for Aging and Developmental Biology, and post-doctoral associate Takahiro Takano, Ph.D., the first author of the paper, has thrown doubt on the assumption by showing that astrocytes are important players in the process too.

Studies by the team in mice show that signaling from astrocytes causes arteries in the brain to expand, bringing about an increase in blood flow.

"When we measure blood flow," said Nedergaard, "it may be that we are not measuring the activity of neurons so much as that of astrocytes."

The idea creates a "chicken or egg" type question in patients with conditions like Alzheimer's or traumatic brain injury where blood flow to parts of the brain plummets.

In Alzheimer's it's known that neurons sicken and die over a period of years. To diagnose the disease, doctors often order a brain scan. When the test shows lessened blood flow, doctors assume that there must be less of a demand for blood, and so significant numbers of neurons in that brain region must have died.

While that still may be true, Nedergaard said, the new results muddy the picture, calling into question any straightforward link between the health of neurons and blood flow.

Nedergaard said that while it is new to find that astrocytes can regulate blood flow, the finding shouldn't be entirely surprising. She said that astrocytes physically touch both synapses – the spaces between neurons that are crucial to brain activity – and blood vessels.

In fact, "footprints" of astrocytes are literally all over blood vessels in the brain: Portions of astrocytes known as "astrocytic endfeet" wrap around nearly all the blood vessels in the brain.

Previously a few scientists have looked at slices of brain tissue and come up with hints that astrocytes might regulate blood flow in brain tissue.

The current research, funded by the National Institute of Neurological Disorders and Stroke, relies on a sophisticated laser system developed by Nedergaard to study the activity of astrocytes in living organisms. The team used a fluorescent dye to light up the blood vessels, then put a special form of the chemical calcium into astrocytes. They used one laser to activate the calcium, and another laser to monitor how astrocytes processed the chemical. They found that astrocytes caused blood vessels to dilate.

Note: In addition to Nedergaard and Takano, the authors of the Nature Neuroscience paper include research assistant professors Guo-Feng Tian and Weiguo Peng; post-doctoral associates Nanhong Lou and Xiaoning Han; and neurosurgery fellow Witold Libionka.

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