For the first time, scientists have neutralized the primary genetic risk factor that causes Alzheimer’s disease. Using human brain cells, scientists at California’s Gladstone Institutes discovered how the gene called APOE4 increases the risk for Alzheimer’s, and also found a potential solution.
There are three different types of the APOE gene — APOE2, APOE3, and APOE4 — and everyone has two copies of the gene. While the E2 version, which is the rarest form, decreases the risk of having Alzheimer’s and the E3 version appears to have no effect on risk, having one copy of the APOE4 gene more than doubles a person’s odds of developing Alzheimer’s. Having two copies increases the risk by 12-fold.
Scientists haven’t known why the APOE4 version is so damaging to brain cells, but Gladstone researchers were able to erase the damage by changing a single molecule, which turned it into a harmless version similar to APOE3.
Currently, most Alzheimer’s research is conducted using mouse models of the disease. But failures once the research reached human trials caused Gladstone scientists to try a different approach.
“Drug development for Alzheimer’s disease has been largely a disappointment over the past 10 years,” says lead author Yadong Huang. “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, Huang and his team decided to use human cells to model the disease and test new drugs. Using induced pluripotent stem cell technology — which is generated directly from adult cells — his team was able to examine, for the first time, the effect of APOE4 on human brain cells.
For their research, they created neurons from skin cells donated by Alzheimer’s patients with two copies of the APOE4 gene, as well as from healthy individuals who had two copies of the harmless APOE3 gene.
They confirmed that the misshapen APOE4 protein is broken down into disease-causing fragments in the cells, causing an accumulation of the protein tau and of amyloid peptides.
While the presence of APOE4 doesn’t change the production of amyloid beta in mouse neuronScientists Fix Gene That Causes Alzheimer’ss, it increases the production of amyloid beta in human cells.
“There’s an important species difference in the effect of APOE4 on amyloid beta,” says the paper’s first author Chengzhong Wang. “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.”
The scientists then tackled the question: How does the presence of APOE4 lead to cell damage?
The researchers examined brain cells that did not produce either form of the APOE protein, and the neurons looked and functioned just like cells with APOE3. However, if the researchers added APOE4, the cells showed characteristics of Alzheimer’s disease. This discovery indicates that the presence of APOE4, and not the absence of APOE3, spurred the disease.
Finally, the researchers looked for ways to repair the abnormalities caused by APOE4. In earlier work, Huang and his collaborators developed a class of compounds that can change the structure of the harmful APOE4 protein so it resembles the harmless APOE3 protein, called APOE4 “structure correctors.”
When they treated human APOE4 neurons with a structure corrector, the signs of Alzheimer’s disease were eliminated, and normal cell function was restored. Huang is now working to improve the compounds so they can be tested in human patients in the future.
More than 5.5 million Americans are currently living with Alzheimer’s disease. It’s the sixth leading cause of death, and its number of victims is growing. The Alzheimer’s Association estimates that by 2050, the number of Alzheimer’s patients could reach 16 million.
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