A new study by Harvard Medical School scientists at Massachusetts General Hospital is offering clues about how to prevent inflammation of brain tissue, which promotes Alzheimer’s disease.
The findings of this study, published in the journal Neuron, could contribute to the development of new therapies for Alzheimer’s disease.
Computer tomography of human brain, from base of the skull to top. Image credit: Department of Radiology, Uppsala University Hospital via Wikimedia, CC0 Public Domain
It’s known that the brains of people with Alzheimer’s fill with deposits of damaged nerve cells and other proteins, known as amyloid plaques, as well as tangled formations of proteins called tau.
“But if you just have plaques and tangles alone, you probably won’t develop Alzheimer’s disease for a long time, if at all,” said Rudolph E. Tanzi, assistant professor of neurology at HMS and the director of the Genetics and Aging Research Unit at Mass General and senior author of the Neuron study.
Rather, explained Tanzi, 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.
Tanzi’s lab discovered the first gene associated with neuroinflammation in Alzheimer’s, known as CD33, in 2008. CD33carries the genetic code for receptors found on microglia, cells that 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 CD33influences the activity of microglia: When the gene is highly expressed, microglia turn from housekeepers to neuron killers, sparking neuroinflammation.
Meanwhile, other investigators identified another gene, TREM2, which has the opposite effect of CD33: It shuts down microglial cells’ capacity to promote neuroinflammation.
In other words, said Tanzi, CD33is the “on” switch for neuroinflammation, while TREM2acts like an “off” switch.
“The Holy Grail in this field has been to discover how to turn off neuroinflammation in microglia,” said Tanzi.
In their most recent inquiry, Tanzi, first author Ana Griciucand their 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. To do that, they posed a question: What happens when these critically important genes are silenced—individually and simultaneously?
To find answers, Tanzi and his team studied laboratory mice specially bred to have brain changes and behaviors consistent with Alzheimer’s. The team began by observing and testing a strain of Alzheimer’s mice that had their CD33genes turned off. They discovered that these mice had reduced levels of amyloid plaque in their brains and performed better than other Alzheimer’s mice on tests of learning and memory, such as finding their way in a maze.
However, when mice had both CD33and TREM2silenced, the brain and behavior benefits disappeared—which also happened when only a single TREM2gene was quieted.
“That tells us that TREM2is working downstream of CD33to control neuroinflammation,” said Tanzi. That theory was bolstered by sequencing microglial RNA, which indicated that both CD33and TREM2regulate neuroinflammation by increasing or decreasing the activity of an immune cell called IL-1 beta and the cell receptor IL-1RN.
“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,” said Tanzi. “We now see that the CD33and TREM2genes are the best drug targets for achieving this goal.”
Source: HMS