The Inconstant Gardener: Microglia, the Same Immune Cells That Help Sculpt the Developing Brain, May Do Damage Later in Life

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Like the cavalry in old Western movies, certain immune cells in the brain rush to answer distress calls and save the day. If a nerve cell is injured or a toxin attacks the brain, these microglia ride to the rescue, moving to the injury site and destroying any bad guys they encounter.

But even in the movies the cavalry, mistakenly or intentionally, sometimes mows down innocent bystanders. A similar scenario may be playing out in the brain with processes that normally limit damage: Microglia may be improperly activated late in life and play a role in neurodegenerative disease.

Take Alzheimer's as an example. People with Alzheimer's disease lose millions of nerve cells in brain areas crucial for memory. As the losses grow, the brain also becomes cluttered with clumps of plaque containing a protein fragment called amyloid-beta, or A-beta. Where these plaques emerge, microglia appear as well.

For years, researchers have believed that the microglia are there to help clear out dead cells and debris left behind as the plaques progressively damage the brain. But new research suggests a different scenario. Long before the plaques collect, microglia may be called in and compelled to attack healthy cells.

A protein called Clq may set up the brain for this destruction. Clq is found in abundance in young brains. During development, the protein works with microglia to target and prune unused connections between brain cells, making way for new connections to form in response to experience and learning.

Clq also accumulates in aging brains, according to recent research. The protein collects at synapses, the junctions between nerve cells where communication between the cells takes place. Information is processed and stored in the brain through these delicate connections. Each nerve cell can have thousands of synapses, creating a total of billions of connections inside the brain.

What impact does accumulating Clq--and its troops, the microglia--have on the older brain?

Stanford neuroscientist Ben Barres speculates that microglia may be reactivated later in life in response to a head injury, stroke or severe illness. This reactivation, he says, may explain the massive loss of neurons seen in neurodegenerative disease.

"Our findings suggest that long before the [nerve] cells die, their synapses are dying," Barres says. "It maybe that the neuron dies only after it has lost a sufficient number of synapses."

His lab and a few others are exploring this hypothesis. They say their findings may implicate microglial cells in an array of conditions, including Alzheimer's, Parkinson's, glaucoma and multiple sclerosis, that result from the loss of large numbers of synapses.

That microglia have the potential to act as both protector and attacker doesn't come as a complete surprise. But whether these immune cells are helpful or harmful in these diseases has remained unclear.

While pruning of synapses during development is necessary for wiring the nervous system, activation of microglia in old age can occur through various means and is a detrimental process, says R. Douglas Fields, chief of the nervous system development and plasticity section at the National Institute of Child Health and Human Development.

"This is somewhat similar to the situation where the action of the body's immune system is normally crucial, but in autoimmune disorders such as multiple sclerosis, pathological consequences can result from the mechanism intended to protect the body," Fields says.

By studying how microglia respond to various proteins and signals in the brain, in both health and disease, scientists aim to clarify microglia's role in synapse loss and disease. Some researchers are also devising ways to tweak microglia's function in the body by inhibiting immune responses that call microglia to action or replacing faulty microglia with healthy ones. …