Researchers identify genetic risk factor for Alzheimer’s

Researchers identify genetic risk factor for Alzheimer’s

PanARMENIAN.Net - A team from the Gladstone Institutes has pinpointed a gene called apoE4 as the potential primary genetic risk factor for Alzheimer’s disease, R&D Magazine reports.

A person is twice as likely to develop Alzheimer’s if they have just one copy of the gene. When someone has two copies, the risk increases by 12-fold, as compared to the most common version of the gene, apoE3.

ApoE4 creates a protein with the same name that differs from the apoE3 protein at only one point, which is enough to alter its main structure and function.

During the study, the scientists were able to erase the damage caused by apoE4 by changing it with a small molecule into a harmless apoE3-like version.

The discovery could ultimately lead to new treatments for Alzheimer’s.

“Drug development for Alzheimer's disease has been largely a disappointment over the past 10 years,” lead author Dr. Yadong Huang, PhD, a senior investigator and director of the Center for Translational Advancement at Gladstone, said in a statement. “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.”

The researchers opted to use human cells instead of mice to model the disease and test new drugs. They were able to create 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 apoE3 gene.

The research team was able to confirm that in human neurons, the misshapen apoE4 protein does not function properly and is broken down into disease-causing fragments in the cells, resulting in a number of problems often found in Alzheimer’s disease, such as the accumulation of the protein tau and amyloid peptides.

While the presence of apoE4 does not change the production of amyloid beta in mouse neurons, in human cells, apoE4 has a very clear effect on increasing amyloid beta production, highlighting the different ways apoE4 controls amyloid beta metabolism in different species.

“There's an important species difference in the effect of apoE4 on amyloid beta,” Chengzhong Wang, PhD, the first author on the paper and a former research scientist at Gladstone, said in a statement. “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 confirming that apoE4 causes damage in human cells, the researchers sought to determine how and why the presence of apoE4 causes damage to human cells.

“It's fundamentally important to address this question because it changes how you treat the problem,” said Huang, who is also a professor of neurology and pathology at UC San Francisco. “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.”

The researchers examined brain cells that did not produce either form of apoE protein and found that the neurons looked and functioned identical to cells with apoE3. When the team added apoE4, the cells became riddled with pathologies related to Alzheimer’s, indicating that the presence of apoE4 and not the absence of apoE3 promotes the disease.

The researchers finally looked for ways to repair the abnormalities caused by apoE4 by treating human apoE4 neurons with a structure corrector to eliminate the signs of Alzheimer’s, restore normal function to the cells and improve cell survival.

Huang and colleagues are now working to improve the compounds so they can be tested in human patients in the future.

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