The rare APOE3-Jacksonville (APOE3-Jac) variant, named after the city in which it was discovered, significantly lowers a person’s risk for developing AD. The function of the APOE protein is to bind and transport lipids, including cholesterol, and mediate fat metabolism. The APOE3-Jac variant has a mutation in its lipid-binding region that allows it to transport more cholesterol and other lipids critical for membrane homeostasis and synaptic function; it increases the amount of healthy fats in the brain. The mutation also keeps APOE3-Jac from clumping together and forming aggregates.
The result of APOE3-Jac’s enhanced lipid-carrying capacity and reduced self-aggregation is a decrease in AD pathology. There are fewer amyloid beta plaques and damaged neurons and less evidence of neuroinflammation. This data opens the door for potential therapies targeting APOE-mediated lipid metabolism and APOE self-aggregation to decrease AD pathology.
A variant – or change in the DNA sequence – of the apolipoprotein E (APOE) gene known as APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD). Not all APOE variants are risk factors; some offer protection, such as the APOE2 variant. The APOE3 variant was previously considered neutral, neither conferring protection nor risk. However, two versions of APOE3 have been identified that may also provide protection from AD: APOE3-Christchurch and APOE3-Jacksonville. (Both variants were named after the city in which they were discovered.)
The rare APOE3-Jacksonville (APOE3-Jac) variant was discovered in 2014. Although it was identified as protective, the underlying mechanisms of how it provided protection were unknown. Recently, researchers in the lab of Cure Alzheimer’s Fund Research Leadership Group member Guojun Bu, Ph.D., found that the mutation reduced the natural tendency of APOE to stick to other APOE molecules, allowing it to better perform its job of transporting lipids. Targeting APOE self-aggregation offers a potential new therapeutic target for treating or preventing AD. The findings were published in Science Translational Medicine.
APOE is primarily produced by astrocytes in the brain. It is a lipid transporter that shuttles cholesterol and other lipids to neurons. This process is critical for the formation and strengthening of synapses. For APOE to perform its important job, it must be in its monomer form and not bound to other APOE molecules as an oligomer.
The missense mutation of APOE3-Jac is located in the region where APOE binds to lipids and other APOE molecules. However, the mutation only alters APOE’s ability to self-aggregate and form oligomers. Because APOE3-Jac is less likely to self-aggregate, it is more readily available to transport lipids.
When the researchers analyzed tissues from post-mortem brains of carriers of APOE3 and APOE3-Jac, they found that APOE3-Jac carriers had less insoluble amyloid beta, which indicates that there were fewer plaques. They also found less soluble Aβ42, the longer “stickier” amyloid beta, which eventually clumps together to form plaques. Similar results were found when the effects of APOE3-Jac were studied in a mouse model of AD. The mouse model also showed decreased plaque-associated immune responses and damaged neurons.
These results indicate that the protection offered by the APOE3-Jac mutation is due to reduced APOE self-aggregation and an increase in APOE’s ability to transport lipids. APOE self-aggregation may contribute to the development of AD, and therefore, targeting the self-aggregation could be a potential new drug therapy.
Dr. Bu sums up the study in an interview with BioWorld Science by saying, “We demonstrated that APOE variants can affect Alzheimer’s disease risk by changing its biochemical properties, which in this case is the aggregation. The lesson learned from the study is that APOE aggregation can contribute to Alzheimer’s pathology pathway. This has led us to consider designing therapeutic strategies that can reduce APOE aggregation and, by extension, reduce the risk of Alzheimer’s disease.”
Science Translational Medicine
Guojun Bu, Ph.D., Independent
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