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Researchers Fix Alzheimer's Gene

For the first time, new breakthrough research shows how well-known genetic risk factors for Alzheimer’s cause signs of the disease in human brain cells. But that’s only the beginning, because researchers were also able to correct the gene and even erase its harmful effects.

For years most of the resources associated with Alzheimer’s research have focused their efforts on the apolipoprotein (APOE) gene and its roll has been studied extensively.

For example, researchers have known for a long time that having one copy of the APOE4 gene variant raises the risk of Alzheimer’s by two to three times.

And, those with two copies of this genetic variant raises the risk by a full 12 times.

The APOE gene’s “normal” role is to provide instructions for creating proteins.

Along with fats, the APOE gene creates lipoproteins, which help to transport and moderate levels of cholesterol in the blood.

The E4 version of the gene however, has been shown to cause damage to the brain.

In fact, several studies like the one recently published in the journal Nature show that this genetic variant increases the risk of toxic proteins like amyloid beta and tau buildup.1

So, what makes the E4 variation of this gene more harmful?

APOE4 studied in human cells for first time

That’s exactly what researchers at Gladstone Institute in San Francisco, CA wanted to know.

To be more specific, they wanted to dive deep and discover the slight differences between the E3 and E4 variants that make the APOE4 variant so deadly.

They wanted to determine if the E4 variant was some how causing the E3 variant to lose certain functions. Or is it simply a case of the APOE4 variant becoming toxic the more abundant it becomes?

Dr. Yadong Huang a professor of neurology and pathology at the University of California, San Francisco and a lead investigator in the study explained it this way.

"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 answers, the research team modeled Alzheimer’s disease in human cells, and examined the effects of APOE4 on those cells. This was the first time this was ever done.

Dr. Huang explained why this disease model was such a significant step towards finding a solution to Alzheimer’s and dementia.

"Many drugs," he says, "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."

Study Hints at A Difference

Dr. Huang and his team applied stem cell technology to skin cells from people with Alzheimer’s who had two copies of the APOE4 gene.

Brain cells were also created using skin cells from people who did not have Alzheimer’s and had two copies of the APO3 gene.

Here’s what they found.

In human brain cells, the APOE4 gene has “pathogenic conformation”. What this means is that it has an abnormal variation that prevents it from functioning properly. This then leads to a series of problems.

According to the authors, “APOE4-expressing neurons had higher levels of tau phosphorylation," which was "unrelated to their increased production of amyloid-[beta] peptides, and [...] they displayed GABAergic neuron degeneration."

They also found something rather significant.

"APOE4 increased [amyloid-beta] production in human, but not in mouse, neurons."

And according to one of the authors of the study:

"There's an important species difference in the effect of APOE4 on amyloid beta”.

This increase in amyloid beta production is not seen in mouse neurons, which may possibly explain some of the discrepancies between mice and humans. This is an important distinction and can play a significant role in the development of drugs in the future.

Fixing the faulty gene

The next thing Dr. Huang and his research team wanted to determine was if the disease was caused by a loss of APOE3 or the accumulation of APOE4.

They did this by comparing neurons that did not produce either the E3 or E4 variants with cells that had the APOE4 added to them.

The cells that did not produce E3 or E4 behaved normally, while those who the APOE4 developed Alzheimer’s-like disease.

This finding confirmed that it’s the presence of APOE4 that in fact causes the disease.

Finally, Dr. Huang and his team then looked for ways they could fix the faulty gene.

Their approach was to apply a previously created APOE4 "structure corrector."

Previous research by Dr. Huang and his team has shown that this “structure corrector”, changes the structure of APOE4 so that it looks and behaves more like APOE3.

Applying this compound to the human APOE4 cells, corrected their defects. This eliminated the disease and restored normal cell function, helping each cell live longer.

In conclusion the research team had this to say:

“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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References:

https://www.nature.com/articles/nature24016

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