In the mitochondria of a neuron, calcium ions are thought to control the production of energy needed for the brain to function. But if there's too much calcium -- as has been suggested to occur in Alzheimer’s disease -- it can cause cells to die. Previous studies have suggested that an imbalance of calcium in neurons might play an important role in the onset of Alzheimer's disease. But how this was linked with mitochondrial dysfunction and neurodegeneration was unclear.
New research led by Pooja Jadiya, a postdoctoral fellow working in John Elrod's lab at Temple University, found that one possible mechanism of Alzheimer’s disease involves the removal of calcium from mitochondria. Calcium ions exit a neuron's mitochondria with the help of a transporter protein called the mitochondrial sodium/calcium exchanger.
The researchers studied samples of human brains taken from Alzheimer's patients. In these diseased tissues, they found that the levels of this exchanger were so low, they were barely detectable. Such low levels caused calcium to build up in the diseased mitochondria. They hypothesized that this may trigger excessive production of reactive oxygen species, molecules known to wreak havoc in the cell and contribute to neurodegeneration. The researchers also found that the reduced activity of this exchanger was associated with impaired energy production and increased cell death, which may contribute to the neurodegeneration that causes Alzheimer's disease.
When the researchers studied mice that were genetically altered to develop Alzheimer's, they found that before the onset of the disease, the gene that encodes the exchanger protein was much less active -- suggesting that a drop in the gene's expression might contribute to disease progression.
To probe this mechanism further, the researchers studied this gene in an Alzheimer’s cell culture model. Like the mice, the cells were genetically altered to exhibit the cellular symptoms of Alzheimer's. When the researchers genetically boosted the levels of the mitochondrial sodium-calcium exchanger, the diseased cells recovered and were nearly identical to the control healthy cells. Production of ATP increased, reactive oxygen species decreased, and fewer cells died.
"No one's ever looked at this before using these model systems," Elrod said. "It’s possible that alterations in mitochondrial calcium exchange may be driving the disease process."
The researchers, including collaborators from the lab of Domenico Praticò, also at Temple University, are now trying to see if they can reverse the development of Alzheimer's in mutant mouse models by ramping up the gene that encodes the sodium-calcium exchanger. If they can, then this mechanism could eventually be the basis for new treatments aimed at boosting the function of the mitochondrial sodium-calcium exchanger, using approaches like 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's the home run," Elrod said. "We're not even close to that, but that would be the idea."
Session 184.29 - Posters: Molecular and Cellular Neuroscience 2186-Pos/B506 - "Genetic rescue of mitochondrial calcium efflux in alzheimer’s disease preserves mitochondrial function and protects against neuronal cell death," is authored by Pooja Jadiya, Alyssa A. Lombardi, Jonathan P. Lambert, Timothy S. Luongo, Jin Chu, Domenico Praticò and John W. Elrod. It will be at 1:45-3:45 p.m. Central Time on Tuesday, Feb. 14, 2017 in Hall B-2 & C of the Ernest N. Morial Convention Center.
ABSTRACT: http://www.abstractsonline.com/pp8/#!/4279/presentation/1268
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