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October 5, 2006

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Gabriel Corfas, Sergio Pablo Sardi, Joshua Murtie, and Samir Koirala
Gabriel Corfas (from left), Sergio Pablo Sardi, Joshua Murtie, and Samir Koirala watch from behind a protective shield as Sardi manipulates a pipette. The team discovered a pathway that is vital for the orderly development of different types of brain cells. (Staff photo Kris Snibbe/ Harvard News Office)

Important signal uncovered in brain development

May be involved in Alzheimer's disease

By William J. Cromie
Harvard News Office

Nobody has counted them, but the best estimates put the number of human brain cells in the trillions. The best known among them, called neurons, do the heavy thinking and remembering. Each of these cells can connect to 10 or more others, forming a vast network of feelings, thoughts, memories, prejudices, and PINS.

But neurons don't do their jobs alone. They are supported and regulated by an immense system of star cells, called astrocytes, because of their shape. New research has discovered how these stars are born. The discovery also hints at how defective astrocytes may contribute to Alzheimer's disease.

It has been known for years that both neurons and astrocytes come from the same brain stem cells. But how do these cells know whether and when to make one or the other?

The distinction is important because astrocytes do many vital things. They promote the formation of synapses, the connections between neurons. Without the right connections and exchange of messages, there would be no memories. The star-shaped cells also regulate how synapses function. For example, they remove excitatory chemicals from the connections, preventing overstimulation that can lead to seizures. They also control the movement of newborn brain cells, which must migrate to the right places for the brain to operate at high efficiency. Finally, astrocytes form the well-known blood-brain barrier that prevents many toxic substances from being carried into your brain by your blood.

Despite these vital functions, little has been known about how stem cells make the right number of each cell type at the right time. Neurons can't make a brain think right without astrocytes, and too many astrocytes would leave some of them with nothing to do. So how is the fate of a brain determined?

After long years of working on the problem, Gabriel Corfas, an associate professor of neurology at Harvard Medical School, and his colleagues at the Neurobiology Program at Children's Hospital Boston, believe they have solved the mystery. In doing so, they found that the process is regulated by a molecule involved in Alzheimer's disease.

Making timely choices

In the Oct. 5 issue of the scientific journal Cell, they report that a neuron-versus-astrocyte decision is controlled by a key protein that extends through the membranes that envelops all brain stem cells. Called receptors, these proteins send signals from the outside of the cell to the inside. In this case, the receptor protein has been given the unmemorable name "erbB4."

Once activated in the stem cell, erbB4 triggers creation of a complex of other proteins that move into the core, or nucleus, of the cell, where its genes sit. The complex then binds to genes that make astrocytes and stifles their expression until star cells are needed. When the time comes for astrocytes to appear on the scene, the proteins relax their inhibiting grip and brain development proceeds.

"During the early stages of brain development, neural stem cells have high levels of the [protein complex], which, through this novel signaling mechanism, prevents or represses the generation of astrocytes," explains Corfas. "As the brain develops, the repression decreases, allowing for the generation of astrocytes."

A big surprise in the research was that the newly discovered function of erbB4 depends on the activity of yet another protein called presenilin, notorious for its role in Alzheimer's disease. Genetic mistakes carried by presenilin are a major cause of the early-onset variety of this debilitating ailment.

Confirming the possibility

At first, this stem cell research was done in test tubes. To be sure that the same process occurs in living animals. the team next did a neat experiment with mice.

To make sure a protein or other molecule does what everyone thinks it does, researchers often "knock out" that molecule to see what happens to a laboratory animal. In other words, knocking out erbB4 would allow the birth of astrocytes at the wrong time, altering the fate of brain development.

In this case, it wasn't easy to knock out erbB4 because it is also vital for heart development. Mice that lack it die before they are born due to heart failure. To get around that, the Harvard team used mice genetically engineered to have erbB4 in their hearts but not their brains.

After the age of 17-18 days, when astrogenesis begins in mice brains, the engineered embryos had brains with a dramatically different makeup from normal mice. They had too many astrocytes and not enough neurons. "These results clearly indicate that erbB4 signaling plays a critical role in controlling the onset of astrogenesis in living animals," points out S. Pablo Sardi, lead author of the study report.

Alzheimer's connection

Scientists consider mice to be good models of most of the biology that goes on in humans. In general, most, if not all, the mechanisms that have been shown to regulate mouse cells appear to be in play in human cells.

That's why the researchers suspect a connection between erbB4 activity in the mouse brain and problem cells in the brains of people with Alzheimer's. "High levels of erbB4 have been found surrounding sticky plaques that clot the brains of those suffering from the disease," Corfas notes. "We need to consider the possibility that defects in erbB4 early in life could result in problems in brain structure that, in the long run, will make it more susceptible to stress or injury."

Since erbB4 contributes to formation of synapses, another possibility to consider is the loss of these critical connections between neurons. "Loss of synapse is one of the earliest events in Alzheimer's," Corfas points out.

Contrary to the old idea that brain cells never replace themselves once they are lost, biologists now know that brain development continues throughout life, albeit at a slower pace. It has been proposed that the brains of Alzheimer's victims are defective in such adult neuron-making. Therefore, Corfas says, "the possibility that erbB4 contributes to the cause, and may thus be a target for treatment, for Alzheimer's and other types of dementia, needs to be further explored."


Copyright 2006 by the President and Fellows of Harvard College