How Genetic Interaction Plays into Alzheimer’s Disease Inflammation

Research that has recently emerged from scientists at Massachusetts General Hospital (MGH) that may help combat Alzheimer’s disease progression. This work emphasized preventing the brain tissue inflammation that leads to symptoms associated with the disease. The MGH team’s findings were recently published online in the journal Neuron.

Alzheimer’s disease is characterized by deposits of damaged nerve cells and proteins known as amyloid plaques, and by tau protein entanglements. These plaques and tangles usually won’t cause Alzheimer’s for a long time if they ever do, according to neuroscientist Rudolph E. Tanzi, PhD, director of the Genetics and Aging Research Unit at MGH. Tanzi was also the senior author of the publication. He claims that the inflammation in the brain associated to these tangles and plaques is what primarily kills neurons and causes cognitive decline.

In 2008, Tanzi and colleagues uncovered the first gene associated with brain inflammation and Alzheimer’s, known as CD33. This gene codes for receptors on microglia cell that normally function to clear neurological debris like these tangles and amyloid plaques.

Tanzi and his associates published their discovery of CD33 in 2013, detailing it’s influence on microglia activity. They found that high CD33 expression induces the microglia to kill neurons rather than simply clear debris. This over-aggression leads to the neuroinflammation seen in Alzheimer’s.

Other work has found a counteracting gene to CD33, known as TREM2. This gene inhibits the microglia’s ability to cause neuroinflammation, opposing the agonistic action of CD33.

“The Holy Grail in this field has been to discover how to turn off neuroinflammation in microglia,” says Tanzi.

Alongside Ana Griciuc, PhD and others, Tanzi set out to identify the interaction between CD33 and TREM2, being that setting a balance between the two genes’ regulations could be key in combatting Alzheimer’s. To analyze each gene, they silenced them both individually and together to observe the effect.

Using mouse models of Alzheimer’s, the team began by turning off the CD33 gene in a sample of the mice. Tanzi and the team noted that these mice not only had lower levels of amyloid plaque built up in their brains, but that they outperformed the other Alzheimer’s mice on memory and learning tests. These tests involve having the mice navigate through a maze.

When both the CD33 and TREM2 genes were silenced, however, these neurological and cognitive benefits ceased. The same effect was observed when the researchers only turned off the TREM2 gene.

“That tells us that TREM2 is working downstream of CD33 to control neuroinflammation,” says Tanzi.

In sequencing the microglia RNA, the researchers found that both the CD33 and TREM2 genes regulate inflammation by manipulating activity of IL-1 and IL-1RN. IL-1 beta is an immune cell involved in the inflammatory response, and IL-1RN is its receptor.

“We are increasingly realizing that to help Alzheimer’s patients, it is most critical to stop the massive brain nerve cell death that is caused by neuroinflammation,” concludes Tanzi. “We now see that the CD33 and TREM2 genes are the best drug targets for achieving this goal.”