Millions of people carry APOE4, the strongest common genetic risk factor for Alzheimer’s disease. New research suggests that this genetic variant may begin changing brain activity and memory circuits years before noticeable cognitive symptoms develop.
Researchers at the Gladstone Institutes have identified a molecular pathway that may help explain how APOE4 affects the brain early in life. Their findings also suggest that some of these changes could potentially be reversed, offering a possible new direction for Alzheimer’s disease treatment.
In a mouse model of natural aging, researchers found that APOE4 increases production of a protein called Nell2. Elevated Nell2 levels cause neurons to become smaller and abnormally active. Mice with the highest levels of brain activity when they were young later developed the most severe memory problems.
When researchers reduced Nell2 production in adult mice carrying APOE4, the neurons returned to a more typical size and firing pattern. The results raise the possibility that future therapies targeting Nell2 could help reduce the harmful effects of APOE4 and lower Alzheimer’s disease risk.
“To our knowledge, this is the first study to directly examine how APOE4 affects the function of neurons at different ages,” says Dr. Mischa Gilberter, principal investigator at Gladstone and senior author of the study. “We discovered that fundamental changes in brain circuitry occurred in young mice that still had normal learning and memory. Importantly, those changes predicted the development of cognitive impairment at older ages.”
APOE4 is a major genetic risk factor for Alzheimer’s disease
APOE4 is one of three common variants of the APOE gene, but it is associated with a substantially higher risk of Alzheimer’s disease than the other variants. Approximately one in four people carries APOE4, and the variant is found in an estimated 60% to 75% of people with Alzheimer’s disease.
“This study is a major advance for Alzheimer’s disease research,” says Yadong Huang, MD, PhD, associate director of the Gladstone Institute for Neurological Diseases and senior author of the study. “It opens the door to a deeper understanding of how APOE4 alters neuronal function at a young age, increases the risk of cognitive decline, and may guide the development of treatments that block the harmful effects of APOE4 early.”
APOE4 causes early overactivity in memory-related brain circuits
Previous studies have identified unusually high brain activity in human APOE4 carriers before middle age. This early neuronal hyperactivity has also been linked to a greater risk of cognitive decline later in life. However, scientists have not fully understood how APOE4 causes these cellular changes or why they may contribute to future memory loss.
To investigate, researchers recorded brain activity in young mice and examined individual neurons in the hippocampus, a brain region essential for learning and memory. Young mice carrying APOE4 showed excessive neuronal activity in two hippocampal regions.
Notably, the same hippocampal region was also found to be overactive in people who carry APOE4.
“We found that the level of hyperactivity in young mice predicted how poorly they would perform on tests of spatial learning and memory later in life,” said Dr. Dennis Tabuena, a scientist co-supervised by Gilberter and Huang and lead author of the study.
The researchers compared the APOE4 mice with mice carrying APOE3, a version of the APOE gene associated with a lower risk of Alzheimer’s disease in humans.
Neurons in the affected hippocampal regions were smaller in APOE4 mice than in APOE3 mice. Smaller neurons are generally more responsive to stimulation and may be more likely to fire excessively.
Hippocampal neurons in APOE3 mice also became more excitable over time, but these changes did not appear until the animals were older.
“This suggests that APOE4 promotes a process similar to normal aging and may help explain why people with this genetic variant are more likely to develop Alzheimer’s disease earlier in life,” Huang says.
APOE4’s effects originate inside neurons
Most APOE4 in a healthy brain is produced by astrocytes, specialized cells that support and protect neurons. Because of this, researchers have long suspected that astrocytes play a primary role in the connection between APOE4 and Alzheimer’s disease risk.
The new findings point to a different mechanism. According to the researchers, APOE4-related hippocampal hyperactivity was caused by APOE4 produced within neurons themselves.
“When we deleted the APOE4 gene from astrocytes, nothing changed,” Gilberter says. “But when we removed it from neurons, the cells grew larger and began functioning normally again.”
Nell2 may be a potential treatment target
The researchers next examined the molecular processes that cause APOE4 neurons to become smaller and more excitable. They analyzed gene activity patterns in individual cells from several cell types in the hippocampus.
The analysis identified Nell2 as a potential key factor. Levels of this molecule were abnormally high in neurons carrying APOE4.
Using CRISPRi, a gene-silencing technique that reduces gene activity without permanently altering DNA, the researchers lowered Nell2 levels in the hippocampal neurons of adult APOE4 mice.
After Nell2 levels decreased, the neurons became larger and less excitable. The findings suggest that elevated Nell2 may contribute to the excessive neuronal activity associated with APOE4.
Nell2 has not previously been studied extensively in connection with APOE4. However, earlier research has shown that Nell2 levels are elevated in the brains of people with Alzheimer’s disease and that higher levels are associated with poorer cognitive function.
“What’s interesting about Nell2 is that by lowering its levels, we were able to reverse disease symptoms in adult mice,” Huang says. “This shows that the damage is not necessarily irreparable and that there may be opportunities for intervention even after the disease process has begun.”
This research was supported by the National Institute on Aging (R01AG061150, R01AG087323, R01AG092390, R01AG085468, R01AG055682, R01AG071697, P01AG073082, F32AG0859612), the National Institute of Neurological Disorders and Stroke (K99NS134734), and the National Center for Research Resources (C06 RR018928).
Source: www.sciencedaily.com