A newly discovered immune cell type may lead to a future treatment for Alzheimer's disease.
Prof. Michal Schwartz of the Weizmann Institute of Science’s Neurobiology Department has shown over the years that mobilizing cells from the systemic immune system does not always cause harm, and in fact, if well controlled, even help in coping with various brain pathologies. But the question regarding the role of the brain's own immune cells, the microglia, remains open: Are they themselves useful? Useless? Or perhaps, harmful?

Schwartz, together with Prof. Ido Amit of the Weizmann Institute’s Immunology Department, and members of their research groups – postdoctoral researchers Drs. Hadas Keren–Shaul and Assaf Weiner, and research students Amit Spinrad, Orit Matcovitch–Natan and Raz Dvir–Szternfeld – now provide an answer to this question, along with a new research approach toward finding ways of treating the disease.

The scientists studied a genetically engineered mouse model of Alzheimer's disease, whose genetic makeup includes five mutant human genes that cause an aggressive form of Alzheimer's disease. A significant obstacle to understanding the roles of immune cells in Alzheimer's and other neurodegenerative diseases is the ability to accurately distinguish between similar cells with different functions, and thus understand which is "friend" and which is "foe." The scientists employed advanced single–cell genomic sequencing technology – a "genetic microscope" developed in Amit's lab in recent years – which enables scientists to fully sequence the genetic material of single cells, allowing them to identify the unique function of these immune cells, even when they are extremely rare – in other words, separating the wheat from the chaff.

In this study, the scientists sequenced the RNA content of all the immune cells in the brains of the Alzheimer’s disease mouse model. Since Alzheimer's is a progressive disease, they repeated this experiment at different points in time along disease progression and compared the results with those from healthy mice. This led them to a fascinating finding: a subset of unique microglial cells not found in healthy mice, which gradually change as the disease progresses. They called these cells disease–associated microglia (DAM).

The scientists found that the development of this unique type of cell depends on the reduction in the expression of regulatory proteins (checkpoints) that restrain microglia activity in the brain, as well as an increase in the expression of a protein complex that recognizes the accumulation of foreign lipids (fat–like molecules) and dead cells, including a protein called TREM2. A mutation in this protein is accompanied by an early – and dramatic – onset of the disease. When the researchers, in collaboration with Prof. Marco Colonna of the Washington University School of Medicine in St. Louis, used a mouse model for Alzheimer's disease that does not express TREM2, the microglia failed to acquire the repair pathways of the DAM cells to remove the beta–amyloid plaques. An examination of the brains of the Alzheimer's mouse model and a postmortem of Alzheimer's patients revealed that these unique cells are located in close proximity with aggregates of brain amyloid "plaques," suggesting a connection between the mechanism that leads to the activation of these unique microglia and their mode of activity. In fact, the newly discovered microglia express many proteins that have been previously classified as disease "risk markers" in Alzheimer's patients, which highlights their important beneficial role in these patients.

These discoveries signify new potential targets in searching for a therapy in Alzheimer’s disease, according to Schwartz.