One study offers clues about preventing brain inflammation in Alzheimer's disease

A new study by Mbadachusetts General Hospital (MGH) scientists provides clues about preventing inflammation of brain tissue, which promotes Alzheimer's disease. The results of this study are online and appear in the September 4, 2019 issue of the journal neuron, could contribute to the development of new therapies for AD.

It is known that the brains of people with AD are filled with damaged nerve cell deposits and other proteins, called amyloid plaques, as well as entangled formations of proteins called tau. "But if you only make plaques and tangles, you probably will not develop Alzheimer's disease for a very long time," said neuroscientist Rudolph E. Tanzi, PhD, director of the research unit. on genetics and aging at the British General Hospital. lead author neuron study. Tanzi explains that it is rather inflammation caused by plaques and tangles, or neuroinflammation, which is the leading cause of neuron mortality, which leads to cognitive decline.

Tanzi's laboratory discovered the first gene badociated with neuroinflammation in AD, called CD33, in 2008. CD33 carries the genetic code of receptors located on microglia cells, which normally act as one of the housewives of the brain, eliminating neurological debris, including plaques and tangles. . In 2013, Tanzi and her colleagues published their finding that CD33 had an influence on microglia activity: when the gene is highly expressed, microglia goes from housekeepers to neuron killers, causing a neuroinflammation.

Meanwhile, other researchers have identified another gene, TREM2, which has the opposite effect of CD33: it blocks the ability of microglia to promote neuroinflammation. In other words, says Tanzi, CD33 is the "on" switch for neuroinflammation, while TREM2 acts as an "off" switch.

The holy grail in this area has been to discover how to disable neuroinflammation in microglia. "

Rudolph E. Tanzi, PhD, Director of the Genetics and Aging Research Unit at the MGH

In their most recent survey, Tanzi, neuroscientist Ana Griciuc, PhD, and their colleagues set out to discover the interactions between CD33 and TREM2 and the role that "crosstalk" might play in neuroinflammation and the origin of the MA. To do this, they asked the following question: what happens when these critically important genes are silenced – individually and simultaneously?

To find answers, Tanzi and his team studied laboratory mice specifically designed to present brain changes and behaviors compatible with AD. The team began by observing and testing a strain of AD mice whose CD33 genes were turned off. They found that these mice had reduced levels of amyloid plaque in their brain and gave better results than other AD mice to learning and memory tests, for example by finding their way into a maze. . However, when the CD33 and TREM2 mice were inhibited, the benefits to the brain and behavior disappeared – which also happened when a single TREM2 gene was inactive. "This tells us that TREM2 is working downstream from CD33 to control neuroinflammation," says Tanzi. This theory was supported by sequencing of microglia RNA, indicating that CD33 and TREM2 regulate neuroinflammation by increasing or decreasing the activity of an immune cell called IL-1 beta and receptor IL-1RN cell.

"We realize more and more that to help patients with Alzheimer's disease, it is paramount to stop the mbadive death of brain nerve cells caused by neuroinflammation," said Tanzi. "We are now seeing that the CD33 and TREM2 genes are the best drug targets to achieve this goal."