Scientists exploring the molecular workings of Alzheimer’s disease have encountered a gene with conflicting roles in the disease’s pathology.
The researchers at the Washington University School of Medicine in St. Louis were looking at a gene called TREM2, known to be a major factor in Alzheimer’s development when mutated. They found that although high-risk TREM2 variants raise the risk of developing Alzheimer's, later in disease progression it can actually be protective against the disease's negative effects. Their study were published this week in Proceedings of the National Academy of Sciences.
TREM2 is present in microglia. When it is absent, microglia can’t generate the energy they need to stop the spread of amyloid beta plaques. In this study, the researchers wanted to learn more about TREM2’s role once plaques have formed.
For their study, the team used mice with a mutant form of human tau that is prone to forming tangles. They then snipped the TREM2 gene out of their study group while leaving it intact for a control group. This meant both groups of mice would develop tau tangles, but only some of them would be missing the gene for TREM2.
At 9 months of age, the brains of mice with tau tangles and TREM2 had shrunk, particularly in areas important for memory, but those without TREM2 had significantly less damage.
The difference in pathologies seemed to stem from the way microglia acted in the diseased brain. Microglia in the TREM2 mice released compounds to fight the disease, but the effect was primarily to injure and kill nearby neurons.
These findings are significant because TREM2 has recently emerged as a target of interest for Alzheimer's treatment. The current study suggests that any attempts to develop a treatment targeting TREM2 should proceed with caution. A treatment that activates TREM2 early in disease and downregulates it later may be the most effective option.
Image: Immune cells are more activated (red) in the brains of mice with the gene TREM2 (left) than in those without the gene (right). A new study shows that having a working copy of the gene TREM2 can reduce risk of Alzheimer's disease under certain conditions but worsen disease in others. Image courtesy of the David Holzman Lab.