Insight Into APOE4 and Alzheimer’s Disease

Posted on June 29, 2018

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Massachusetts Institute of Technology researchers have begun new research into APOE4, a variant of the APOE gene known to cause early-onset Alzheimer’s disease.

APOE is the gene responsible for the production of apolipoprotein, a necessary protein that combines with fat to create lipoproteins.

Lipoproteins help to transport fat and cholesterol through the bloodstream.

There are three known variants of the APOE gene: APOE2, APOE3 and APOE4. These variants are found in more than 50 percent of the country’s population and are prevalent in people living with Alzheimer’s disease.

Having the APOE4 genetic variant translates to a three times higher risk of developing Alzheimer’s disease.

The presence of APOE4, in particular, is one of concern to Alzheimer’s researchers. This variant of APOE has been found to increase the chances of developing early-onset Alzheimer’s disease. Individuals with APOE4 variants can have one variant or two variants of the gene. The presence of more variants increases the risk of developing Alzheimer’s disease.

Why does APOE4 increase the risk of developing Alzheimer’s disease so significantly?

It increases the risk of developing the disease because it causes the development of beta-amyloid proteins in the brain. Beta-amyloid proteins are a component of sticky protein brain plaques that block signals from traveling between nerves of the brain.

The Boston researchers discovered that APOE4 had a significant influence in every type of cell they analyzed regarding the development of Alzheimer’s.

The cell types examined during the study included neurons, astrocytes and microglia. The cells researchers used were created using induced pluripotent stem cells (iPSCs) that had been coaxed into developing into these specific neural cell types.

Induced pluripotent stem cells are adult stem cells that have been reprogrammed to an embryonic-like state and then instructed to develop into different types of cells.

“Adult stem cells are very versatile cells. They can be instructed to develop into many different types of cells for treating a range of health conditions,” said Dr. Joel Singer, a New York stem cell physician.

Once the iPSCs developed into the neural cells, the MIT researchers edited the cells using CRISPR/Cas9 gene editing and converted cells with the APOE3 variants to become APOE4 variants.

The researchers noted that gene expression varied significantly in neural cells that expressed APOE4: Expression of 250 genes went down, while 190 genes went up.

In astrocyte cells, the fluctuations in gene expression were more significant, and microglia cells showed 1,100 genes with decreased expression and 300 genes reflected an increase in expression.

Neurons that had the APOE4 variant grew more synapses. Synapses are the junction between nerve cells in which impulses pass through. Neurons with additional synapses were also found to have higher levels of amyloid proteins than neurons that did not have the APOE4 mutation.

Astrocytes with the APOE4 variant had higher levels of cholesterol than astrocytes with APOE3. APOE4 astrocytes had a reduced ability to eliminate amyloid proteins in comparison to APOE3 astrocytes.

APOE4 microglia cells also showed reduced ability to remove amyloid proteins as well as viruses and bacteria compared to APOE4 microglia.

During their researchers, the MIT study authors also found that the damaging effects of the APOE4 variants were reversible when exposed to APOE3-containing microglia.

The project’s leaders hope that by understanding more about the impact of APOE4, they can develop new treatments and preventative measures in individuals with the APOE4 variant.

Their research is exciting for Singer.

“Alzheimer’s disease is a serious life-altering condition, and the ability to reverse or prevent its onset would be a significant benefit to a large part of our population,” Singer said.

Alzheimer’s disease affects almost 5.7 million Americans, and 14 percent of those living with Alzheimer’s disease have APOE4.

 

Sources:

Alz.org. 2018 ALZHEIMER’S DISEASE FACTS AND FIGURES.

R&D Magazine. New Study Sheds Light on Gene Linked to Alzheimer’s. 1 June 2018.