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What hundreds of biomolecules tell us about our nerve cells

The mammalian brain is a complex structure of interacting regions that typically have highly specific functions including cognition, motor functions, emotions and information processing. Each region contains millions, sometimes billions of neurons and different types of glial cells such as astrocytes, oligodendrocytes and microglia. Together, they orchestrate the brain’s functions. For proper functioning, the connections between regions are key to relay specific information and trigger certain behaviour. The number of cellular connections between nerve cells in every human brain is estimated to be more than 100 trillion. The enormous complexity of all the interacting elements in the brain requires us to look at the disease process, like those of Alzheimer’s and Parkinson’s disease, in the brain as a whole using mammalian animal models.

Neurodegenerative processes such as those occurring in Parkinson’s disease are characterised by pathological changes of the brain cells, often specific to certain areas of the brain: These cells lose their structure and function and thereby their connectivity, a process that is accompanied by changes in their metabolism. Until now, many scientists have focused on just one or a few aspects of the disease to better describe and understand the underlying mechanisms.

Researchers at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg recently set out to realize a more global approach: They analysed hundreds of biomolecules, referred to as the metabolome, produced by nerve cells in different regions of the mouse brain. In the process, they looked not only at healthy brains, but also at brains in which neurodegeneration occurs.

The 3D anatomy of the brain is crucial for creating this snapshot of its physiology, ruling out experiments in cell cultures or less complex organisms such as yeast or worms. In humans such studies can only be performed in post mortem tissue of people who donated their brain to a brain bank. Studying metabolic changes due to neurodegeneration over time as done in this study would not be possible in humans. As the mouse brain is structurally similar to the human brain, the researchers expect to find similar metabolic differences in the human brain.

The researchers dissected upper, middle, and lower brain regions of mice with different stages of neurodegeneration induced through injection of a neurotoxin. To study the metabolite signatures of the brain, they used gas chromatography coupled to mass spectrometry. These analytical chemistry techniques are particularly suitable for analysing samples from complex tissues and discovering of both known and still unknown biomolecules in those tissues.

After the measurements, the researchers used a bioinformatics approach known as Machine Learning to specifically derive the metabolic profile of each brain region. They discovered that certain combinations of different molecules reflect specific functional states of nerve cells in each brain region. By comparing their observations with microscopic analysis of disease processes in nerve cells, the LCSB researchers could show which particular metabolic profile is associated with the degeneration of these cells.

"Our observations are important, on the one hand, for paving the way for the discovery of new ways of diagnosing neurodegeneration and, on the other hand, for the development of new drugs to fight diseases such as Parkinson’s or Alzheimer’s," says Dr. Manuel Buttini, Head of the Neuropathology study. “Analysing metabolite profiles rather than just microscopic cellular changes or individual biomolecules can lead to a better understanding of the effect of novel therapeutics for brain diseases.”

This study benefited from the joined efforts of experts from quite different fields: mouse neurobiology, biochemistry, molecular biology, and bioinformatics came together to enable the successful completion of the study. It has been published in the American Journal of Pathology.

The LCSB neuropathology platform works in close collaboration with the mouse facility. Together, they bring in their expertise to study pathological changes on macroscopic, microscopic and molecular level in mouse models of Parkinson’s and Alzheimer’s disease.