A little-understood type of cell vital to the brain's development could also have a hand in the formation of neurodegenerative disorders like Alzheimer's disease, a growing body of research argues.

Microglia, a type of immune cell, account for about 7 percent of all brain cells. The possible connections between the cells and disease are not fully comprehended, but experts say microglia's role in the brain's maturation means they could play a part when problems emerge.

"One may be forgiven for concluding that our understanding of microglial biology is lacking, despite decades of research in this area," said a review article published this month in Science. "Yet, compelling experimental and clinical evidence exists in support of the notion that microglia act as both 'bad cop' and 'good cop' in distinct circumstances."

Scientists have long known that microglia are responsible for the brain's immune response, wolfing down invading pathogens or engulfing and clearing out old or damaged cells.

"We always think of them as the garbage collecting cells in the brain," said Dr. Ben Barres, chairman of neurobiology at Stanford and an author of the Science article, titled "Microglia: Scapegoat, Saboteur, or Something Else?"

But researchers have discovered that microglia likely help clean up in a different way. As the brain develops, it builds more synapses - or connections between neurons - than necessary, and the extra bonds need to get pruned away. Barres likened the process to how a sculptor has to remove excess clay from the finished product.

In the brain's case, it is thought that the microglia do the trimming of the extra synapses. Proteins, called complement proteins, tag weaker synapses and set off what is known as a "complement cascade," resulting in the microglia separating the connections.

Synaptic pruning slows as the brain matures, researchers said. But evidence suggests the complement cascade and microglia can get reactivated years later and start killing off synapses that should be left alone, contributing to the synapse loss seen in people with Alzheimer's disease.

Much more research needs to be done, but Barres said that if the complement cascade contributes to synapse loss, then a treatment that stops the cascade can protect some of the synapses.

Connections broken

Some Alzheimer's drugs have targeted the clumps of protein known as plaques that form around neurons, but Barres said they have generally failed to stop the brain's degeneration. He thinks that the complement process that leads to synapse loss may occur earlier in the disorder's development, so halting that could prove more effective.

Barres partnered with former Genentech researcher Arnon Rosenthal to start a company, Annexon, in 2011 devoted to developing such treatments. Annexon researchers will be looking at therapies for Alzheimer's and other neurodegenerative disorders, which all show weakened synaptic bonds among neurons.

"The first thing that goes down is the complexity of the connections," said Rosenthal, who in 2001 founded Rinat Neuroscience, which Pfizer acquired in 2006. "The wiring basically becomes simplistic," resulting in the cognitive decline that plagues Alzheimer's patients.

Dean Hartley, the director of science initiatives at the Alzheimer's Association, said the treatment approach is promising, but that there are unknowns at play. For example, neuroinflammation, which occurs when microglia and a number of other cells and molecules become activated, is present in people with Alzheimer's. But Hartley said it was unclear if neuroinflammation contributes to the disease or is a result of the disorder.

'Chicken or egg' first

"The problem is the chicken or egg phenomenon," Hartley said. "We really haven't established well when it comes in the Alzheimer's disease process, but it's likely that under certain circumstances, it's initiating the disease, and in other cases, it's secondary."

In addition to factoring in neurodegenerative disease, microglia may play a role in some developmental disorders tied to errors in synaptic pruning, scientists suspect. If that is the case, understanding microglia has the potential for new treatments for these diseases that emerge at the beginning of life.

"Because microglia sculpt neural circuits, can dysfunction contribute to neurodevelopmental or psychiatric disorders?" Barres and his colleagues wrote in the review article. "In an unexpected paradigm shift, immune cells may play a crucial role in diseases that are traditionally considered to be neuronal, including autism-spectrum and obsessive-compulsive disorders."
