In a mouse model for Alzheimer’s disease, two key microglial receptors CD33 and TREM2, exert opposite effects on microglial activity and amyloid-beta pathology. Knocking out CD33 in this model had a beneficial effect by increasing microglial activation. Knocking out TREM2 using genetic manipulation of the mouse model, on the other hand, had the opposite effect. The cognitive performance and presence of pathological amyloid plaques worsens and the microglial activation is reduced.
(News release published by Massachusetts General Research Institute)
BOSTON – A new study by scientists at Massachusetts General Hospital (MGH) offers clues about how to prevent inflammation of brain tissue, which promotes Alzheimer’s disease (AD). The findings of this study online now and appearing in the September 4, 2019 print issue of the journal Neuron, could contribute to the development of new therapies for AD.
It’s known that the brains of people with AD 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,” says neuroscientist Rudolph E. Tanzi, Ph.D., director of the Genetics and Aging Research Unit at MGH, and senior author of the Neuron study. Rather, explains 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 AD, known as CD33, in 2008. 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.
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, says Tanzi, CD33 is the “on” switch for neuroinflammation, while TREM2 acts like an “off” switch. “The Holy Grail in this field has been to discover how to turn off neuroinflammation in microglia,” says Tanzi.
In their most recent inquiry, Tanzi, neuroscientist Ana Griciuc, Ph.D., and their colleagues set out to discover how CD33 and TREM2 interact, and what role that “crosstalk” might play in neuroinflammation and the origin of AD. 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 behavior consistent with AD. The team began by observing and testing a strain of AD 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 AD 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,” says 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.
“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,” says Tanzi. “We now see that the CD33 and TREM2 genes are the best drug targets for achieving this goal.”
The primary authors of the Neuron paper are Ana Griciuc, Ph.D., an assistant professor of Neurology at MGH and Harvard Medical School (HMS); and Rudolph Tanzi, Ph.D., vice-chair of the Department of Neurology and director of the Genetics and Aging Research Unit at MGH, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Tanzi is also scientific advisor for and an equity stakeholder in AZTherapies, a Boston-based company that is testing a drug designed to reduce neuroinflammation called ALZT-OP1 in a phase III clinical trial.
The research has also been highlighted in a piece by Mark Terry on Biospaces entitled “Two Genes Appear to Act as On/Off Switches for Neuroinflammation and Alzheimer’s Disease
As the beta-amyloid theory of Alzheimer’s disease fades from prominence, many researchers are turning their attention to the role of inflammation. Although beta-amyloid is still very much a factor in the disease, many believe that it is an uncontrolled or faulty inflammatory and immune reaction to beta-amyloid that causes the majority of the cognitive damage. As a result, many researchers are shifting focus to the role of microglial cells, which are specialized immune cells in the central nervous system, and the potential use of anti-inflammatories in prevention and treatment.
Researchers with Massachusetts General Hospital (MGH) have identified some crosstalk communication between TREM2 and CD33, two genes that play a role in inflammation and Alzheimer’s disease. CD33 carries the genetic code for receptors on microglia cells. TREM2 has the opposite effect, shutting down microglia’s ability to promote neuroinflammation.
Rudy E. Tanzi, director of the Genetics and Aging Research Unit at MGH and senior author of the study, which appeared in the Neuron, says that CD33 is the “on” switch for neuroinflammation and TREM2 is the “off” switch.
“The Holy Grail in this field has been to discover how to turn off neuroinflammation in microglia,” Tanzi stated.
At the heart of the research was the question, what happens if the genes are silenced, simultaneously or individually?
Studying laboratory mice specially bred as Alzheimer’s disease models, the scientists tested started by looking at a strain of AD mice whose CD33 genes were turned off. These mice had decreased levels of beta-amyloid in their brains and did a better job in various learning tests, like running a maze. But when CD33 and TREM2 were silenced, the benefits disappeared. That also happened when a single TREM2 gene was silenced.
“That tells us that TREM2 is working downstream of CD33 to control neuroinflammation,” Tanzi stated. “
Further, they sequenced microglia RNA, which showed that both CD33 and TREM2 regulate neuroinflammation by increasing or decreasing the activity of a type of 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,” Tanzi stated. “We now see that the CD33 and TREM2 genes are the best drug targets for achieving this goal.”
(image courtesy of the National Institutes of Health / National Institute of Aging)