2004 New Investigator Research Grant

Microglia are specialized cells in the brain that act as a kind of sentry for the immune system. They may serve as “front-line defenders” or as “recruiters” of other immune-system agents.

These cells are activated early in the course of Alzheimer’s disease, but their function is not well understood. It is unclear whether (1) activated microglia might be good for “eating up” beta-amyloid, a key suspect in Alzheimer’s; (2) activated microglia might be bad because they recruit immune-system cells that lead to potentially harmful long-term inflammation; or (3) microglia might be best “turned on” at some times and “turned off” at others.

Benoit Melchior, Ph.D., and colleagues have observed that in regions of the brain severely affected by Alzheimer’s disease, certain microglia have numerous cell-surface proteins called TREM-2, which are particularly sensitive to beta-amyloid. Based on experiments with cells, the researchers have hypothesized that TREM-2 is a kind of “switch” that results in microglia being less effective at destroying beta-amyloid and more effective at enlisting immune-system “fighters,” called T cells, which cause inflammation.

In the current work, the investigators will study in cell cultures how TREM-2 regulates the function of microglia. They will also assess the impact of blocking TREM-2 activity in mice genetically altered to develop an Alzheimer-like disorder. This research may clarify the effect of immune-system responses on Alzheimer pathology and predict the outcome of potential Alzheimer therapies that enlist the immune system.