Scientists from the Gladstone Institutes have discovered how apoE4 increases a person's risk for Alzheimer's disease and how to get rid of the damage it has caused. Their work was published this week in Nature Medicine. 

"Drug development for Alzheimer's disease has been largely a disappointment over the past 10 years," says lead author Yadong Huang, M.D., Ph.D. "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." 

So in Huang's lab, they decided to use human cells as their model for the disease. Using iPSC technology, the team was able to create neurons from Alzheimer's patient skin cells with two copies of apoE4 gene and cells from healthy individuals who had two copies of the apoE3 gene. 

The team confirmed that in human neurons the apoE4 protein doesn't function properly and is broken down into fragments that cause Alzheimer's. The nonfunctioning apoE4 protein results in the accumulation of amyloid peptides and tau protein, which are both indicators of Alzheimer's disease. 

Interestingly, the presence of apoE4 protein does not change the production of amyloid beta in mouse neurons, but it does in human cells. 

"There's an important species difference in the effect of apoE4 on amyloid beta," says Chengzhong Wang, Ph.D., the first author on the paper. "Increased amyloid beta production is not seen in mouse neurons and could potentially explain some of the discrepancies between mice and humans regarding drug efficacy. This will be very important information for future drug development."

After the team confirmed that apoE4 does in fact cause damage in human cells related to Alzheimer's disease, they came to the following questions:

  1. How does the presence of apoE4 lead to cell damage?
  2. Is the presence of apoE4 resulting in a loss of normal apoE3 function, or does the addition of apoE4 cause the toxic effects? 

"It's fundamentally important to address this question because it changes how you treat the problem," explains Huang. "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. 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."

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To find out the answers, the researchers looked at brain cells that didn't produce either type of apoE protein and those neurons looked and functioned like cells with apoE3. However, when they added apoE4, the cells started to show indicators of Alzheimer's disease. From this finding, they found that it was the presence of apoE4 and not the absence of apoE3 that promotes disease. 

Lastly, the team wanted to see if they could correct the abnormalities caused by apoE4. In early work, Huang and collaborated developed compounds called structure correctors that could change the structure of apoE4 protein so that it would look like apoE3 protein. So when they treated the human apoE4 neurons with structure correctors, signs of Alzheimer's disease disappeared and normal function was restored. 

Huang is now working with collaborators in academia and the pharmaceutical industry to improve the compounds so they can be used in human patients.