By altering a gene associated with Alzheimer’s, researchers have been able to effectively neutralize it in tests and eliminate signs of the disease in lab-grown neurons.
The gene in question is called apoE4 and has been associated with the build-up of the tau tangles and beta-amyloid plaques that are linked to the devastating disease. Previously, studies looking into this connection and attempting to create drugs to target it have been mired in problems, mainly as they have tended to focus on mouse models rather than human cells.
“Drug development for Alzheimer's disease has been largely a disappointment over the past 10 years,” explained Yadong Huang, who led this latest study published in Nature Medicine. “Many drugs work beautifully in a mouse model, but so far they've all failed in clinical trials. One concern within the field has been how poorly these mouse models really mimic human disease.”
In light of this, the team turned to using human cells in the lab, and took the skin cells from patients with Alzheimer’s who have two copies of apoE4 as well as samples from people with the normal variant known as apoE3, and turned them into stem cells. These were then coaxed into forming human neurons.
From this, the researchers were able to study exactly how the apoE4 gene variant influences the build-up of the tau proteins and beta-amyloid plaques that are associated with the development of Alzheimer’s. After finding that yes, it does indeed cause this build-up to occur, they then wanted to know how: does the presence of apoE4 causing a loss of apoE3 function, or is it itself causing the toxic effects seen? These answers are vital as to how we might treat the problem.
“If the damage is caused due to the loss of a protein's function, you would want to increase protein levels to supplement those functions,” said Huang. “But if the accumulation of a protein leads to a toxic function, you want to lower production of the protein to block its detrimental effect.”
The lab-grown human neurons were able to prove that it was indeed the presence of apoE4 – and not simply the absence of apoE3 – that caused the damaging proteins to build-up in the cells. This meant that the researchers could use earlier work they had done in altering the abnormal apoE4 gene to resemble the innocuous apoE3 gene, using what are called “structure correctors.”
By targeting the gene in this way, they were in effect able to neutralize it and restored normal function to the neurons. They now hope to work with drug companies to see if they are able to translate what they found into a treatment that can then be put through clinical trials.