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Established Alzheimer’s Risk Gene Has a New Role

Established Alzheimer’s Risk Gene Has a New Role

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Dendritic fragments from ApoE3, top, and ApoE4, bottom, mature adult-born granule cells. Credit: Kernie lab/CUIMC

A new study has found that a gene that raises the risk of getting Alzheimer’s disease stunts the development of neurons created during adulthood in a part of the brain involved in learning and memory.

The finding may help explain how the gene, called ApoE4, leads to the emergence of cognitive decline in many adults who carry the gene.

Understanding adult neurogenesis, the process that generates new neurons in the adult brain, could help researchers harness this function to treat neurodegenerative diseases like Alzheimer’s and brain injuries.

Background

ApoE is one of the most studied genes of all time. One version of the gene, ApoE4, is the strongest known genetic risk factor for Alzheimer’s disease. (About 10 percent to 20 percent of the population carries ApoE4).

It’s thought that ApoE4 increases the risk of Alzheimer’s disease by increasing the amount of toxic amyloid in the brain, but some studies suggest the gene may have other effects on the brain.

“We know that the ApoE gene produces a cholesterol-transport protein, but how the ApoE4 version contributes to Alzheimer’s disease is still a mystery,” says Steven Kernie, MD, professor of pediatrics at Columbia University Vagelos College of Physicians and Surgeons.

In addition to its role in Alzheimer’s, ApoE4 has also been associated with diminished recovery from traumatic brain injury, which in turn has been associated with impairments in the brain’s ability to produce new neurons.

What the researchers did

Kernie and colleagues set out to find how ApoE4 influenced the formation of neurons in adult brains.

The researchers studied mice with and without ApoE as well as mice with human ApoE3 and ApoE4. They then looked at the development of new neurons in the animals’ hippocampus, a region of the brain involved in learning and memory. 

What the researchers found

Adult mice without any ApoE or with the human ApoE4 gene produced new neurons, but the neurons did not mature normally. These neurons had short and sparse branches compared with neurons produced by mice with the human ApoE3 gene. The ApoE4 neurons also had fewer spines, where connections are made with other neurons.

This suggests that human ApoE3 is better than ApoE4 at helping new neurons grow, branch out, and form connections with other neurons. 

What the findings mean

“Continuous formation of new neurons is important for maintaining a healthy, functioning hippocampus,” says Kernie.

“Our study shows that ApoE4 compromises neurogenesis in mice. This suggests that ApoE4 may impair the ability of the hippocampus to develop normally and respond to injury.”

Further research is necessary to understand how ApoE4’s impact on neurogenesis influences Alzheimer’s disease in people.

More details

Steven Kernie is also director of the Division of Pediatric Critical Care Medicine at Columbia University Irving Medical Center.

 

The paper, “ApoE Regulates the Development of Adult Newborn Hippocampal Neurons,” was published in eNeuro on July 30, 2018.

 

Other authors: Yacine Tensaouti, Elizabeth P. Stephanz, and Tzong-Shiue Yu (all Columbia University Vagelos College of Physicians and Surgeons).

 

This research was supported by the National Institutes of Health (grants R56NS089523 and R01NS095803).

 

The authors declare no competing financial interests.

 

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