Brain 3D mapping to combat neurodegenerative disease

Brain proteomics in 3D: Abundance profiles of four different proteins (of more than 1,000 proteins) compiled from 1-millimeter cubes (voxels) in a mouse brain. The boxes correspond to the locations of the voxels in the brain, and the colors represent their relative abundance in each region (from high, red, to low, violet).

Wanda felt a jolt of frustration run through her when her husband forgot to meet her at the clubhouse after their round of golf. How many times had this happened lately" It was becoming an embarrassment.

Later that evening, Wanda noticed that Robert seemed to be staring at the TV rather than watching it. She was becoming concerned. He had been a bit moody lately in addition to his increasing forgetfulness. Were these symptoms of something serious, she wondered" Neither Robert nor Wanda was prepared for the devastating news that Robert had Alzheimer’s disease, a progressive brain disorder that gradually destroys a person’s memory and ability to learn, reason, make judgments, remember specific words and even carry out daily activities. As Alzheimer’s progresses, individuals may also experience changes in personality and behavior. Today, more than 5 million people in the United States are living with Alzheimer’s disease. The cost of caring for people with the disorder is $100 billion per year in the United States alone.

Although currently no cure for Alzheimer’s exists, new treatments are on the horizon as a result of increasing insight into the biology of the brain. Research now being performed at DOE’s Environmental Molecular Sciences Laboratory may accelerate the development of a cure for Robert and others with neurodegenerative disorders such as Alzheimer’s, Parkinson’s or multiple sclerosis through advanced 3D mapping of brains.

As part of their research, scientists at Pacific Northwest National Laboratory have demonstrated a technological platform for spatial mapping of mouse brain proteins. The protein map is “the first to apply quantitative proteomics to imaging,” says Richard D. Smith, Battelle Fellow at PNNL.

A key challenge in neuroscience derives from the molecular complexity of the brain; about one-third of the mammalian genome appears to be dedicated exclusively to brain function. Armed with information such as the types and locations of biomolecules within the mammalian brain—the organ with the most complicated 3D structure—scientists can begin to understand the origin and progression of brain diseases. Current imaging techniques provide only limited protein identification— typically, only one or a few proteins at a time—in spite of good spatial resolution technology.

For the first time ever, scientists have been able to detect over 1,000 different proteins in a single experiment and map them to the brain structures. “Proteins are the lead actors, the most important part of the picture,” PNNL’s Smith says. “They are the molecules that do the work of the cells.” To produce the map, the team of scientists characterized brain pieces in scores of small 1-millimeter cubes, or voxels, to see where proteins appear in the brain and where they vary in abundance. By labeling all proteins from another mouse brain, they developed reference points to compare the amounts of protein in the different parts of the brain and from one mouse to another. Their research represents a step toward the complete characterization of the detailed spatial abundance patterns of the brain proteome and provides a methodological basis for future studies. The integrated methodology includes tissue voxelation, automated microscale sample processing, use of reference samples for quantification, high-throughput analysis and a strategy for identifying proteins based on precisely measured masses of the molecules using advanced mass spectrometers.

The next steps for this team of researchers are to use their methodology to develop a 3D visualization of an entire mouse brain and then compare proteome maps for healthy brains with others whose protein portraits look different. Because contrasts in location and abundance of proteins may display the earliest detectable stages of neurological diseases, scientists hope neurodegenerative diseases such as Alzheimer’s might be curbed if caught and treated early enough, giving patients and their families a new hope.