The immune system’s contribution to the progression of Alzheimer’s Disease (AD) has become a growing topic in neurodegenerative research. In a new study led by Neurobiology and Behavior Associate Professor Mathew Blurton-Jones and doctoral student Amanda McQuade, a team of international scientists have demonstrated novel roles for the AD risk gene TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) in microglia derived from human induced pluripotent stem cell (iPSC). Their study revealed new functions of this immune receptor in human cells that could play a critical role in the development and progression of AD.
Microglia are the brain’s primary immune cells and play an essential role in maintaining proper brain health. Nevertheless, microglia and the immune responses they elicit have been implicated in the development of AD neuropathology.
Recent genetic studies on AD risk loci have implicated several previously unknown immune genes expressed by microglia. One of those genes is the TREM2 receptor, which consists of a receptor signaling complex that can trigger the recognition and response to brain pathologies and lipids. In the current study, Professor Blurton-Jones and Ms. McQuade sought to examine the AD-associated functions of TREM2 in human microglia.
“Many of the genes that influence the risk of developing AD are highly expressed in microglia,” Professor Blurton-Jones said. “Yet how these genes influence microglial function remains unclear. While mouse studies can be helpful, human microglial genes are often quite different from the mouse versions of these genes.”
Using a patented method to generate human microglia developed in the Blurton-Jones lab, the team differentiated microglia from isogenic CRISPR-modified TREM2-knockout iPSC lines. Functional analyses of the cells in vitro and transplanted within the brains of AD model mice revealed that TREM2 deletion harms microglial function. The team observed reduced microglial survival, impaired phagocytosis of key substrates including apolipoprotein E, and inhibition of cell-mediated chemotaxis, all of which culminated in an impaired response to the AD relevant beta-amyloid plaques that develop in the mouse model.
“These studies tell us that microglia use TREM2 to sense and migrate toward AD pathology. When they reach the amyloid plaques, the microglia surrounding them and help to reduce further neuronal injury. However, if microglia have a genetic problem with TREM2 it dramatically impairs this protective response. These data also suggest that if drugs can be developed that can increase TREM2 they could help to slow the progression of AD,” says Professor Blurton-Jones.
You can find the full study online in Nature Communications.