Identification of axonal transport deficits may aid in early detection, treatment
Early detection of Alzheimer's disease and development of therapeutics are the research goals of Dr. Robia Pautler, assistant professor in the Department of Molecular Physiology and Biophysics at Baylor College of Medicine.
She is using a technique she helped develop called Manganese Enhanced MRI (MEMRI) neuronal tract tracing. It can be used to measure in vivo axonal transport rates in mouse models of human disease. Deficits in this transport system have been identified in mouse models of Alzheimer's with mutated forms of amyloid precursor protein, which are in part responsible for amyloid plaques that are found in the brains of those suffering from Alzheimer's disease.
Preventing cognitive decline
Axonal transport is a cellular process that is responsible for movement of cell parts to and from a neuron's cell body. It is also responsible for moving molecules destined for degradation. Axonal transport occurs throughout the life of a neuron and is essential to its growth and survival.
"In the lab setting we have identified these axonal transport deficits before any sign of plaques. Our hope is to eventually get this test into the clinical setting. This will allow us to detect the disease early on before there is a significant amount of cognitive decline," said Pautler, who is also an assistant professor in the departments of neuroscience and radiology at BCM.
Manganese Enhanced MRI allows researchers to assess the same animal before and during disease progression by following the transport of manganese ion. The ion can enter neurons through calcium channels and then is transported along microtubules by the axonal transport system.
Understanding transport system
In trying to determine how the transport system is affected by the onset of Alzheimer's disease, researchers began to investigate reactive oxygen species (ROS). ROS are molecules that form as a natural byproduct of normal oxygen metabolism. They found that ROS dramatically increased in the Alzheimer's disease mice models.
Most recently, Pautler, her colleagues at BCM and collaborators at New York University found that a potent antioxidant enzyme known as SOD2, made in the cell's mitochondria, reduced levels of ROS in the mouse models of Alzheimer's disease.
"What was the most amazing part of this discovery was that with the reduction of ROS we saw a significant reduction in plaque formation and a complete recovery in axonal transport rates and blood flow," Pautler said.
New direction for treatment
The findings directly link mitochondrial superoxide to the disabling effects of Alzheimer's, she said. It also shows that a mitochondrial anti-oxidant enzyme has a beneficial effect, providing new direction for treatment of the Alzheimer's disease.
Reduced ROS as a result SOD2 overexpression also led to a reversal of hyperphosphorylation in an enzyme that is responsible for helping to regulate cerebral blood flow.
"Again what we are seeing is that ROS formation might be that one stick that we need to pull out to cause AD pathology to come tumbling down," Pautler said.
Her team of researchers and collaborators are now pursuing novel therapies that will mimic a SOD2 overexpression.