ALZHEIMER
For the first time, how the most well-known genetic risk factor for Alzheimer's disease causes signs in human brain cells and also, the scientists who managed to correct the gene and erase its harmful effects.
The apolipoprotein (APOE) gene
in the development of Alzheimer's and its complex role has been studied
extensively. For instance, researchers know that having one copy of the
APOE4 gene variant raises the risk of Alzheimer's by two to three times.
And, having two copies of this genetic variant puts people at a 12-fold
higher risk. Normally, APOE's role is to provide instructions for
creating the protein of the same name. In combination with fats, APOE
creates lipoproteins, which help to transport and regulate levels of cholesterol throughout our bloodstream.
However, the E4 version of the gene seems to be particularly damaging to the brain, with several studies showing that this genetic variant increases the risk of toxic amyloid beta and tau
buildup. But why is that? What makes the E4 variant of this gene so
much more harmful than other variants? Researchers at the Gladstone
Institutes in San Francisco, CA, wanted to find out. Their findings have
just been published in the journal Nature Medicine.
More specifically, the researchers wanted to locate and understand
the fine yet crucial difference between the E3 and E4 variants that
makes the APOE4 gene so devastating.
Is it a case, the researchers wondered, of the E4 variant making
APOE3 lose some of its functions? Or is it the case that more APOE4 has
toxic effects?
Lead investigator Dr. Yadong Huang — a professor of neurology and
pathology at the University of California, San Francisco — explains the
importance of this question.
"It's fundamentally important," he says, "to address this question
because it changes how you 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." "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."
To find out, the researchers modeled the disease in human
cells, examining the effect of APOE4 on human brain cells for the first
time. Dr. Huang explains why changing the disease model was, in itself, a
huge step for Alzheimer's research. "Many drugs," he explains, "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."
Applying stem cell
technology to skin cells from people with Alzheimer's who had two
copies of the APOE4 gene, Dr. Huang and his team created neurons. The
researchers also created brain cells using skin cells from people
who didn't have Alzheimer's and had two copies of the APOE3 gene. The
scientists found that in human brain cells, the APOE4 protein has
a "pathogenic conformation" — meaning that it has an abnormal form that
prevents it from functioning properly, leading to a series of
disease-causing problems. Namely, "APOE4-expressing neurons had higher
levels of tau
phosphorylation," the authors write, which was "unrelated to their
increased production of amyloid-[beta] peptides, and [...] they
displayed GABAergic neuron degeneration." Importantly, they also found that "APOE4 increased [amyloid-beta] production in human, but not in mouse, neurons." "There's an important species difference in the effect of APOE4 on amyloid beta," explains first study author Chengzhong Wang.
CORRECTING FAULTY GENE
Next, Dr. Huang and team wanted to see whether it was the loss of APOE3 or the accumulation of APOE4 that caused the disease. So, they compared neurons that did not produce either the E3 or the E4 variant of the protein with cells that had APOE4 added to them.The former continued to behave normally, while adding APOE4 led to Alzheimer's-like pathologies. This confirmed the fact that it is the presence of the APOE4 that causes the disease.
As a final step, Dr. Huang and his team looked for ways in which to fix the faulty gene. To this end, they applied a previously developed APOE4 "structure corrector." The so-called structure corrector has been shown in previous research, led by the same Dr. Huang, to change the structure of APOE4 so that it looks and behaves more like the inoffensive APOE3.
Applying this compound to human APOE4 neurons corrected the defects, thereby eliminating signs of the disease, restoring normal cell function, and helping the cells to live longer.
The researchers conclude:
"Treatment of APOE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of APOE4 is a viable therapeutic approach for APOE4-related [Alzheimer's disease]."
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Reference: https://www.medicalnewstoday.com/articles/321455.php
