Researchers have determined how much energy is produced in two regions of the brain, each of which plays important roles in the development of diseases, including Alzheimer’s disease, Huntington’s disease and Parkinson’s disease. The results show that these brain regions do not produce the same amount of energy, and this may help to provide greater insight into how the diseases develop.
Nerve cells use incredible amounts of energy to communicate with each other and for other purposes. When the energy supply to the nerve cells cannot meet the demand, the nerve cells die, and this can result in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease.
New Danish research shows that different regions of the brain, each of which plays a specific role in developing the three diseases, do not produce the same amount of energy although the regions contain the same quantity of molecular power stations (mitochondria) in the nerve cells. This means that each of these mitochondria must work harder in one region of the brain than in the other.
This discovery may be important for understanding the diseases and is important in any case in relation to research on the brain in general.
“Since we know that different brain regions behave differently, keeping this in mind is important when performing experiments with mouse brains, for example, and when making conclusions about their energy production. Which region of the brain you examine turns out to be very relevant,” explains the researcher behind the study, Anne Nørremølle, Associate Professor, Department of Cellular and Molecular Medicine, University of Copenhagen.
The new research results were recently published in Neuroscience.
Nerve cells use enormous amounts of energy
Anne Nørremølle’s research primarily focuses on understanding the reasons why Huntington’s disease and other neurodegenerative diseases affect certain regions of the brain.
One important aspect is to understand how nerve cells function at the molecular level.
The main function of the nerve cells is to transmit signals to each other through either electrical impulses or neurotransmitters so that, for example, a pain signal may flow from the hand to the brain and back again, thereby alerting you to remove your hand from something hot before being seriously burned.
These signals require enormous amounts of energy, which also means that the tips of the nerve cells – the synapses, where the signals transition from one nerve cell to the other – are filled with mitochondria, the cells’ power stations that convert energy into ATP.
The production, separation and subsequent collection of neurotransmitters require energy. Insufficient energy to run these processes damages the synapses, which can lead to nerve cells degenerating. When this happens, neurodegenerative diseases arise, and that is why Anne Nørremølle focuses on how the synapses produce energy to maintain their function.
“A whole group of neurodegenerative diseases seems to have energy-deficient nerve cells, and this helps explains how the diseases develop,” explains Anne Nørremølle.
Many neurodegenerative diseases affect two brain regions
Anne Nørremølle, Maria Hvidberg Petersen and their colleagues wanted to determine whether the energy production differs in the synapses in the regions of the brain typically affected by Parkinson’s disease, Huntington’s disease and Alzheimer’s disease.
The relevant regions are the striatum, which is deep inside the brain and coordinates many of our more or less conscious behavioural patterns, and the cerebral cortex: the region that plays a key role in memory, attention, perception, awareness, thought, language and consciousness.
The various diseases affect the striatum and the cerebral cortex at different stages. Sometimes the striatum is affected first and sometimes the cerebral cortex.
Researchers do not yet fully understand how these very complex diseases develop, but they can see that, for example, in the hereditary types of the diseases, an avalanche effect is often initiated, which ends up affecting the ability of mitochondria to produce the energy the nerve cells require.
“We therefore asked ourselves whether the synapses in these two regions behave differently and whether this can help to explain some of the characteristics that emerge as the diseases develop. Perhaps these differences can explain why one disease first manifests itself in the striatum and then the cerebral cortex, whereas another disease does the opposite,” says Anne Nørremølle.
Separating mouse brains
Anne Nørremølle and her colleagues examined brains from mice.
They dissected the mouse brains into the different regions and examined the striatum and the cerebral cortex separately. They then carefully separated the synapses from the rest of the cells by gently mashing the tissue.
One thing they examined under a microscope was the synapses, after staining the mitochondria green to determine how many mitochondria the nerve cells in the different brain regions have.
They found that the synapses in the nerve cells in the cerebral cortex contained about as many mitochondria as those in the striatum.
They then examined the synapses by using an Agilent Seahorse analyser that can measure the energy produced, even in microscopic samples. Among other things, the analyser measures the amount of oxygen that mitochondria use when they break down nutrients to create ATP.
One brain region is less efficient than the other
The results showed that, although the cerebral cortex has the same number of mitochondria in the synapses, they have to run at higher speed because they produce more energy than the mitochondria in the synapses in the striatum.
The study also showed that the mitochondria in the synapses in the cerebral cortex are a little less efficient and leak more protons in the process, whereas the mitochondria in the synapses in the striatum are very precise and well regulated in producing energy.
“It is still too early to conclude what this means, but we speculate that the speed at which the synapses produce energy may be important when the nerve cells have to resist negative effects of the kind that can lead to nerve cell damages and ultimately to neurodegenerative diseases,” says Anne Nørremølle.
The next step is just around the corner
Anne Nørremølle and colleagues have already taken the next step in their research on the importance of the differences in how the synapses produce energy.
One thing the researchers are now examining is the precise significance of the discovery for the hereditary disorder Huntington’s disease.
The researchers are finalizing an article on their results from a study in which they examined the energy production of the two regions of the brain in a mouse model of Huntington’s disease.
“The aim is to see whether healthy and sick mice differ in how the synapses produce energy and whether this can explain why and how specific nerve cells are affected in this disease,” says Anne Nørremølle.
“Functional differences between synaptic mitochondria from the striatum and the cerebral cortex” has been published in Neuroscience. A co-author is Niels Henning Skotte, postdoctoral fellow, Proteomics Program, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
