Researchers discover how genes promote neuroinflammation, cognitive decline
“Crosstalk” between genes may be responsible for brain inflammation in Alzheimer’s disease, according to a new study by scientists at Massachusetts General Hospital (MGH) in Boston, and published in the journal Neuron.
Rudolph Tanzi, PhD, senior author and director of the Genetics and Aging Research Unit at MGH, studied laboratory mice specially bred to have brain changes and behavior consistent with Alzheimer’s disease.
It is known that the brains of people with Alzheimer’s disease fill with deposits of damaged nerve cells and other proteins, known as amyloid plaques, as well as tangled formations of proteins called tau, Tanzi said. Plaques and tangles alone do not necessarily lead to Alzheimer’s disease, he said, but rather it's the inflammation that occurs in response to plaques and tangles, or neuroinflammation, that is the primary killer of neurons, which leads to cognitive decline.
In 2008, Tanzi's lab discovered CD33, the first gene associated with neuroinflammation in Alzheimer’s disease. CD33 carries the genetic code for receptors found on microglia cells, which normally act as one of the brain's housekeepers, clearing away neurological debris, including plaques and tangles. In 2013, Tanzi and colleagues published their discovery that CD33 influences the activity of microglia. When the gene is highly expressed, microglia turn from housekeepers to neuron killers, sparking neuroinflammation, Tanzi said.
Meanwhile, other investigators identified another gene, TREM2, which has the opposite effect of CD33. It shuts down microglia's capacity to promote neuroinflammation. In other words, CD33 is the "on" switch for neuroinflammation, while TREM2 acts like an "off" switch, Tanzi said.
In their most recent inquiry, Tanzi and colleagues set out to discover how CD33 and TREM2 interact, and what role that "crosstalk" might play in neuroinflammation and the origin of Alzheimer’s disease. To do that, they posed a question, what happens when these critically important genes are silenced--individually and simultaneously?
The team began by observing and testing a strain of Alzheimer’s disease mice that had their CD33 genes turned off. They discovered that these mice had reduced levels of amyloid plaque in their brains and performed better than other Alzheimer’s disease mice on tests of learning and memory, such as finding their way in a maze. However, when mice had both CD33 and TREM2 silenced, the brain and behavior benefits disappeared, which also happened when only a single TREM2 gene was quieted.
"That tells us that TREM2 is working downstream of CD33 to control neuroinflammation," said Tanzi.
That theory was bolstered by sequencing of microglia RNA, which indicated that both CD33 and TREM2 regulate neuroinflammation by increasing or decreasing activity of an immune cell called IL-1 beta and the cell receptor IL-1RN, Tanzi said.
"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," he said. "We now see that the CD33 and TREM2 genes are the best drug targets for achieving this goal."