Gene Variant Linked to Alzheimer’s Disease Speeds Up Brain Inflammation
A gene variant, associated with Alzheimer’s has been discovered that speeds up brain inflammation and kills brain cells.
The results published in Nature, name the variant as APOE4 protein. Neuroscientist David Holtzman of Washington University School of Medicine in St Louis and colleague carried out the research.
“The paper is a tour de force,” said Robert Vassar, a neuroscientist at Northwestern University Feinberg School of Medicine in Chicago. “It’s a seminal study that’s going to be a landmark in the field” of Alzheimer’s research.
Researchers are already aware that people who carry the E4 version of the APOE gene are at an increased risk of developing Alzheimer’s. A version of the gene called APOE3 has no effect on Alzheimer’s risk, whereas the APOE2 version protects against the disease. Molecular details for how APOE protein, which helps clear cholesterol from the body, affects brain cells are not understood.
However, Holtzman and other researchers previously demonstrated that plaques of amyloid-beta protein build up faster in the brains of amyloid-beta protein build up faster in the brains of APOE4 carriers. Having A-beta plaques isn’t enough to cause the disease, Holtzman explains. Tangles of another protein called tau are also required. Once tau tangles accumulate, brain cells begin to die and people develop dementia. In a number of new experiments, Holtzman, and colleagues now are able to show for the first time, that there’s also a link between APOE4 and tau tangles.
In one particular experiment, mice that had no A-beta in their brains developed more tau tangles if they carried the human version of APOE4 than if they had the human APOE3 gene, Holtzman and colleagues found. That specific finding highlights APOE4 affects tau independently of A-beta.
As a conclusion, people who died from various diseases caused by tangled tau had more dead and damaged cells if the people carried APOE4. The researchers also tracked 592 people who had low levels of A-beta in their cerebral spinal fluid, a clue that plaques have formed in the brain, and who showed symptoms of Alzheimer’s. During a five to ten year period, the disease progressed 14% faster in people with one copy of APOE4 and 23% faster in people with two copies than in people who didn’t have that version of the gene, the researchers discovered. Those with worsening symptoms are presumed to be caused by an increased build-up of tau angles in the APOE4 carriers.
Furthermore, APOE4 seems to make Alzheimer’s worse by causing inflammation, the researchers found. Such inflammation can make brain degeneration worse. Molecular neurobiologist, Sangram Sisodia of the University of Chicago, explains that the data linking the APOE4 gene tbraio tau tangles and brain inflammation is “super tight”. However, the molecular details behind how APOE4 protein causes those effects are still vexingly absent. Much more work is needed to uncover which molecules APOE4 interacts with, so that researchers can devise ways to counteract its negative effects in the brain.