![[brain illustration]](https://cdn1.medicalnewstoday.com/content/images/articles/315/315833/brain-illustration.jpg)
Mitochondria – sometimes referred to as the “powerhouse of the cell” – are small structures that transform energy from food into cell “fuel.”
In the mitochondria of a brain cell, calcium ions control how much energy is produced for the brain to function. Previous research has shown that an excessive production of calcium can cause neurons to die, therefore linking a calcium imbalance with the neurodegenerative process involved in Alzheimer’s disease.
Until now, however, the exact mechanism that links Alzheimer’s-related neurodegeneration and mitochondrial calcium imbalance was unknown. The new research – led by Pooja Jadiya, a postdoctoral fellow at Temple University in Philadelphia, PA – sheds light on this association.
The study was carried out by researchers from the Center for Translational Medicine at Temple University, and the findings were presented at the 61st Meeting of the Biophysical Society in New Orleans, LA.
Jadiya and colleagues studied brain samples from Alzheimer’s patients, a mouse model genetically modified to replicate Alzheimer’s-like symptoms, and a mutant Alzheimer’s-affected cell line.
They examined the mitochondrial alterations in calcium processing, together with reactive oxygen species (ROS) generation, the metabolism of the active amyloid precursor protein, membrane potential, and cell death. They also looked at the activation of the mitochondrial permeability transition pores and oxidative phosphorylation.
In a healthy brain, calcium ions leave a neuron’s mitochondria to prevent an excessive buildup. A transporter protein – called the mitochondrial sodium-calcium exchanger – enables this process.
In Alzheimer’s-affected tissue, Jadiya and team found that the sodium-calcium exchanger levels were extremely low. In fact, the protein was so low that it was difficult to detect.
The researchers hypothesized that this would cause an overproduction of ROS, which would, in turn, contribute to neurodegeneration.
ROS are molecules that, in high levels, have been shown to damage proteins, lipids, and DNA, thus causing oxidative stress.
The team did find a correlation between the reduced activity of the sodium-calcium exchanger and increased neuronal death.
Additionally, in the mouse model, the scientists found that right before the onset of Alzheimer’s, the gene that encodes the exchanger was significantly less active. A decrease in this gene’s expression further suggests that the protein exchanger plays a key role in the progression of the disease.
Finally, the scientists also tested this mechanism in an Alzheimer’s-affected cell culture model, by artificially boosting the levels of the exchanger.
As hypothesized, the affected cells recovered to a point where they were almost identical to healthy cells. Furthermore, the levels of adenosine triphosphate (ATP) increased, the ROS levels decreased, and fewer neurons died.
ATP is a molecule considered to be the “energy currency of life” by some biologists, as it is required by every activity our body engages in.
John Elrod, a co-author of the study, explains the significance of the findings:
“No one has ever looked at this before using these model systems. It is possible that alterations in mitochondrial calcium exchange may be driving the disease process.”
The study may also pave the way for new treatment options, Elrod explains. The team is currently working to reverse the neurodegeneration typical of Alzheimer’s disease in mouse models by stimulating the expression of the gene that encodes the sodium-calcium exchanger. This could be achieved with new drugs or gene therapy.
“Our hope is that if we can change either the expression level or the activity of this exchanger, it could be a viable therapy to use early on to perhaps impede Alzheimer’s disease development – that is the home run,” Elrod says. “We are not even close to that, but that would be the idea.”