Scientists Discover and Fix Genetic Risk Factor of Alzheimer’s Disease

  • Scientists discover how to eliminate the primary genetic risk factor of Alzheimer’s disease –  Apolipoprotein E. 
  • They examined the effect of apolipoprotein E on human brain cells for the first time. 
  • To fix this faulty gene, they applied previously built compounds – “structure correctors”.

Researchers at Gladstone Institutes (housed at San Francisco General Hospital) show, for the first time, how one of the major genetic risk factors of Alzheimer’s disease causes signs in human brain cells. Also, they have managed to fix this gene and remove its dangerous effects.

The role of apolipoprotein E (ApoE) gene in the progression of Alzheimer’s has been extensively studied. It’s a type of protein involved in the fat metabolism. It also generates lipoproteins for transporting and regulating the cholesterol levels throughout the bloodstream.

So far, we know that one copy of this gene increases the risk of Alzheimer’s by 2 to 3 times. And having two copies raises the risk by 12-fold. 

The ApoE4 gene produces a protein of the same name, which differs from the ApoE3 protein at only one aspect  – ApoE3 has Cys112, whereas ApoE4 has Arg112. The single difference is enough to change the structure as well as the function of the gene. But what makes this gene so much dangerous than other variants? Let’s try to find out.

ApoE4 Tested On Human Cells (for first time)

Most research and development on Alzheimer’s disease are done in mouse models. Over the past decade, these studies have given us nothing but disappointments.

As a matter of fact, many drugs work perfectly in mouse models, but they fail in clinical trials, meaning mouse models don’t exactly mimic human disease. This forced researchers to turn to other models.

This time, they used human cells to test new drugs. They analyzed the effects of ApoE4 on human brain cells.

How Did They Do It? 

Scientists created 2 classes of neurons: one from healthy people with two copies of the ApoE3 gene, and another from Alzheimer’s patients who had two copies of the ApoE4 gene.

They found that the ApoE4 gene has a ‘pathogenic conformation’ in human brain cells. It’s an abnormal form, which obstructs the gene from working properly, leading to some serious problems usually found in Alzheimer’s disease.

More specifically, neurons produced from Alzheimer’s patients had higher levels of tau phosphorylation, which is not related to their increased growth of amyloid-beta peptides, and they showed degeneration GABAergic neuron. Importantly, this effect occurs in human cells only.

Reference: Nature Medicine | doi:10.1038/s41591-018-0004-z | Gladstone Institutes

Increased amyloid-beta peptide growth is not observed in mouse neurons. This could explain most of the inconsistencies between human and mice regarding efficacy of drugs. Also, the research provides some crucial data for future drug development.

Repairing the Faulty Gene

Brain - Genetic Risk Factor of Alzheimer's Disease

One of the most important questions is how exactly does ApoE4 cause cell damage. Researchers wanted to see whether it was the accumulation of ApoE4 or loss of ApoE3 that caused the disease.

So, they examined brain cells that didn’t create either the ApoE4 or the ApoE3 protein, and the neurons functioned and looked just like cells with ApoE3. However, adding ApoE4 led to Alzheimer’s-like pathologies. This shows that the presence of ApoE4 causes disease (not the absence of ApoE3)

Now, to fix this faulty gene, scientists applied previously built compounds, named “structure correctors”, that can alter the ApoE4 structure so it behaves more like the harmless ApoE3 protein.

Read: Super-Resolution Microscopy Can See Cells In Both Space & Time

This technique completely removed the signs of Alzheimer’s and improved survival of cells. The team is currently working to further enhance the structure correctors so they can be applied to humans in the future.

Written by
Varun Kumar

Varun Kumar is a professional science and technology journalist and a big fan of AI, machines, and space exploration. He received a Master's degree in computer science from Indraprastha University. To find out about his latest projects, feel free to directly email him at [email protected] 

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