By Rachel Tompa, Ph.D. / Allen Institute

Your brain contains multitudes.

The spongy, folded mass is made up of hundreds or thousands of different kinds of cells, many of which remain at least partly a mystery to scientists. The more researchers look, the more they uncover.

Now, a team of neuroscientists from the University of California, Los Angeles, led by Allen Distinguished Investigator Baljit Khakh, Ph.D., has found even more multitudes within one specific class of brain cell, known as astrocytes. These cells, which are smaller than neurons but visually just as complex, were originally discovered more than 150 years ago and named after stars for their radiating, starburst shapes.

Khakh and his colleagues found that not only are there several different types of astrocytes that are specialized for different regions of the brain, but that their very complexity may be important in keeping brains healthy. Khakh and his colleagues published a study describing their results in the journal Science today.

Some of the genes known to be linked with Alzheimer’s disease in humans turn out to underlie astrocytes’ complex, bushy shapes. When the team artificially removed such genes in astrocytes in the laboratory mouse, the astrocytes became visually simpler, and the mice performed more poorly on a memory task. They also found that in a mouse model of Alzheimer’s disease, astrocytes have a simpler, less branching shape.

Scientists have long thought that astrocytes play a role in Alzheimer’s — as well as in many other brain diseases — but this is the first time that their 3D shape, or morphology, has been implicated in the disease. This finding points to a potential avenue for a new kind of Alzheimer’s therapy, Khakh said, one aimed at restoring astrocytes’ normal functions in the brain by attempting to restore their complex shapes.

“If these morphologies get simpler in Alzheimer’s disease, then if we could restore that morphology, this may restore the cells’ normal support functions,” he said.

Maintaining signal fidelity

While all of astrocytes’ jobs are not fully understood, the cells are thought to act as regulators in the brain. They appear to help maintain the brain’s signal fidelity by cleaning up extra signaling molecules at synapses, the specialized connections between neurons. When one neuron sends these molecules to another neuron, the astrocytes form a physical barrier, keeping those chemical signals contained so they only reach their target neuron without accidentally broadcasting that signal farther than intended. If astrocytes were missing, the signaling molecules could diffuse through the brain, potentially activating many other neurons and muddling what was once a precise message.

Despite their complexity and their importance, little was understood about how astrocytes might vary across the brain. Different brain regions carry out different functions and it’s known that types of neurons vary from region to region.

“Historically, astrocytes have been viewed as a universal glue, almost like a homogenous morass of cells that exists everywhere in the brain, but everywhere is the same morass,” Khakh said. “We found that view unsatisfactory, so we decided to test it.”

The team used a method known as transcriptomics that assesses genes switched on in individual astrocytes to categorize them into discrete types, studying cells from 13 different regions of the mouse brain. This technique has been used extensively at the Allen Institute and elsewhere to categorize neurons and other kinds of brain cells into discrete types.

The scientists found that astrocytes from different parts of the brain indeed had different gene signatures. They were able to group the mouse astrocytes, based on the genes the cells switched on, into seven different kinds.

Currently, the scientists are working to understand how Alzheimer’s-risk genes are tied to astrocyte shape complexity. Ideally, they’d identify a molecule involved in astrocyte complexity that could be targeted by new drugs, Khakh said. But because the brain — and its associated diseases — is so complex, it’s unlikely that a single drug targeting astrocytes will work on its own against Alzheimer’s.

“The brain is a highly evolved, complex, multicellular organ. Our exploration of how the brain works must also include a multicellular understanding of how it’s built,” Khakh said. “Complex diseases like Alzheimer’s that affect multiple parts of the brain, and multiple kinds of cells, will likely also require a multi-prong attack.”

The Allen Distinguished Investigator awards are funded by the Paul G. Allen Family Foundation. The Paul G. Allen Frontiers Group, a division of the Allen Institute, recommends funding and supports the administration of the awards.