Targeting the APOE gene may one day prevent brain damage in people at risk of Alzheimer’s.
The APOE gene, responsible for encoding a protein called apolipoprotein E, is known to dramatically raise the risk of Alzheimer’s.
In fact, the E4 variant of the gene is “the most prevalent genetic risk factor” for Alzheimer’s, with over half of people with the condition having this gene expressed.
Recent research has focused on understanding the role of APOE in Alzheimer’s formation. For instance, Medical News Today have recently reported on a study led by Dr. David Holtzman, head of the Department of Neurology at the Washington University School of Medicine in St. Louis, MO.
In that very study, Dr. Holtzman uncovered the mechanism by which the APOE protein amplifies Alzheimer’s disease-related brain damage in mice, and he suggested that future research should focus on targeting the protein to nip the neurodegenerative process in the bud.
Now, in the new study, Dr. Holtzman has done exactly that. Together with Ph.D. student Tien-Phat Huynh, Dr. Holtzman and colleagues reveal that a molecule called an “antisense oligonucleotide” interferes with the production of the APOE protein, which leads to significantly less brain damage.
The DNA-based molecule was created by study co-author Tracy Cole, Ph.D., and the findings are now published in the journal Neuron.
Antisense oligo halves brain damage in mice
Dr. Holtzman and his team used a mouse model of Alzheimer’s disease. They injected the molecule into the brains of newborn mice that were genetically designed to be predisposed to the disease. A control group of newborn mice was administered either saltwater or a placebo “oligo.”
APOE protein levels were halved by the molecule in the mice that were given it, compared with control mice.
After 2 months, the rodents received another boost of the treatment or another boost of saltwater depending on their group. Another 2 months later, the mice’s brains were examined.
By this point — when the mice were 4 months old — they would have developed plaques of the sticky amyloid-beta protein, a known hallmark of the disease.
However, the mice that had been treated with the antisense molecule had half as many amyloid plaques as the mice that received saltwater. Additionally, each plaque caused only half as much neuronal damage in the intervention group compared with the saltwater group, suggesting the molecule successfully staved off Alzheimer’s-related neurodegeneration.
Given the success that the molecule had in prevention, the team also wanted to see whether the compound would yield any benefits if administered after the plaques had formed.
APOE ideally targeted before plaques form
Therefore, this time they administered the molecule to 6-week-old mice that had developed amyloid beta plaques, and they gave saltwater to a control group.
Although the experiments revealed no reduction in the actual number of beta-amyloid plaques or in the amount of the damaging protein, the results did show that each plaque caused only half as much neuronal damage in the oligo compound group compared with the saltwater group.
Dr. Holtzman comments on the findings, saying, “If you wanted to target APOE to affect the amyloid process, the best thing would be to start before the plaques form.”
“But even if you start later, you still may reduce the amount of damage caused by the plaques. Now that we have shown that it is possible to target APOE, we can start figuring out the best way to do it.”
Dr. David Holtzman
“Our findings indicate that APOE is not just involved in Alzheimer’s risk and disease progression, but it could potentially be a real target for treatment or prevention,” concludes Dr. Holtzman.
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