|Alzheimer’s patients often have neurofibrillary tangles caused by build-up of tau proteins. Image via Wikimedia Commons|
One difficulty in finding new therapies for neurological disease is that scientists can’t peer inside a living neuron and watch how its DNA and proteins work–or fail to work. Researchers at Gladstone Institutes recently used stem cell techniques to overcame that problem and got a glimpse of how cellular processes go awry and cause diseases like Alzheimer’s.
The research team focused on understanding how a group of proteins called tau proteins operate in cells. Diseases caused by problems with tau proteins are grouped together in a category called “tauopathies,” the most famous of which is Alzheimer’s Disease. One defining characteristic of tauopathies is that neurons have an unhealthy build-up of tau, which scientists think leads to neuron deterioration over long periods. A genetic mutation has been identified which predisposes people to this build-up of tau protein. Efforts to understand the deterioration tau causes have been stymied by the fact that it’s nearly impossible to observe neurons in action.
Taking skin cells from a person with this genetic mutation, the team created induced pluripotent stem cells (iPSCs) and generated neurons that had the genetic mutation. In some of the cells they replaced the defective gene with a healthy gene, which allowed them to compare the effects of the defective and healthy genes in cells side by side in a lab dish. They published the results of this work in the August 29 Stem Cell Reports.
Our research showed that the Tau produced by neurons from people with the Tau mutation is different; so it is red-flagged by the cell and targeted for destruction. However, instead of being flushed out, Tau gets chopped into pieces. These potentially toxic fragments accumulate over time and may in fact cause the neuron to degenerate and die.
The neurons with the spliced normal gene didn’t have the tau fragment build-up and continued to operate normally.
The study’s first author, Helen Fong, is a CIRM postdoctoral scholar and the Huang, the senior author, is also a CIRM grantee .
This is one more example of how researchers using stem cells to create a model of the disease outside the body can help us understand what’s going on inside our bodies. Knowing what goes wrong is the first step to finding drugs to reverse the damage.
Ours Alzheimer’s Fact Sheet has more information about the Alzheimer’s disease research we fund.