LivingThey knock out the main gene associated with Alzheimer's

They knock out the main gene associated with Alzheimer's

Groundbreaking research shows, for the first time, how the best-known genetic risk factor for Alzheimer’s disease creates certain signals in human brain cells. In addition, scientists have managed to correct the gene and erase its harmful effects. Without a doubt a great step for science.

The complex role of the apolipoprotein gene (APOE) in the development of Alzheimer’s has been extensively studied. We already know, for example, that having one copy of the APOE4 gene variant increases the risk of Alzheimer’s by two to three times, and having two copies of this genetic variant increases the risk 12 times more.

In combination with fats, APOE creates lipoproteins, which help transport and regulate cholesterol levels in our bloodstream. However, the E4 version of the gene appears to be particularly damaging to the brain, with several studies showing that this genetic variant increases the risk of toxic accumulation of beta amyloid and tau.

But why does this happen? What makes the E4 variant of this gene so much more harmful than other variants?

Researchers at the Gladstone Institutes in San Francisco, California (USA) wanted to find out; more specifically, the researchers wanted to locate and understand the difference, albeit crucial, between the E3 and E4 variants that makes the APOE4 gene so devastating.

“If the damage is caused by the loss of function of a protein, you will want to increase protein levels to supplement those functions. But if the accumulation of a protein leads to toxic function, you will want to reduce the production of the protein to block its damaging effect, “explains Yadong Huang, leader of the work to the journal Nature Medicine.

To find out, the researchers modeled the disease in human cells and examined the effect of APOE4 on human brain cells for the first time. Huang explains why changing the disease model was, in itself, a big step for Alzheimer’s research.

“Many drugs work wonderfully in mice, but so far all have failed in clinical trials . One concern in the field has been how poorly these mouse models mimic human disease,” Huang clarifies.

Differences between mice and humans

By applying stem cell technology to skin cells from people with Alzheimer’s that had two copies of the APOE4 gene, the experts created neurons; also using skin cells from people without Alzheimer’s that had two copies of the APOE3 gene.

The scientists discovered that in human brain cells, the APOE4 protein has a “pathogenic conformation ,” meaning it has an abnormal shape that prevents it from working properly, leading to a number of disease-causing problems.

Importantly, they also found that APOE4 increased beta-amyloid production in humans, but not in rodent neurons.

“There is a significant difference between species in the effect of APOE4 on beta amyloid,” says Chengzhong Wang, a co-author of the study.

“Increased beta amyloid production is not seen in mouse neurons and could explain some of the discrepancies between mice and humans with respect to drug efficacy. This will be very important information for future drug development. “.

Reference: Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Chengzhong Wang, Ramsey Najm, Qin Xu, Dah-eun Jeong, David Walker, Maureen E. Balestra, Seo Yeon Yoon, Heidi Yuan, Gang Li, Zachary A. Miller, Bruce L. Miller, Mary J. Malloy & Yadong Huang. Nature Medicine (2018). DOI: doi: 10.1038 / s41591-018-0004-z

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