TREM2 Antibodies as an Immunotherapy for Alzheimer's Disease
Researchers here report on preliminary evidence that antibodies binding to TREM2 can enhance the ability of the immune cells known as microglia to clear out debris and metabolic waste in brain, particularly the amyloid-β plaques thought to contribute to the progression of the condition. Given the unremitting record of failure to date for amyloid-β clearance approaches to produce material benefits in patients, it is something of a question as to whether more and better clearance is what is needed right now. From a reductionist point of view, amyloid-β aggregates should indeed be removed, as their presence is a material difference between old and young brains. That doesn't mean that amyloid-β is necessarily the primary driver of the disease state, however. Perhaps its contribution will only become clear once the other pathologies of Alzheimer's disease have been addressed: neuroinflammation, tau aggregates, and vascular dysfunction.
Researchers have identified a specific antibody that binds to the brain's immune cells, termed "microglia". This stimulates their activity in such a way that they live longer, divide more quickly and detect aberrant substances more easily. In mice with disease symptoms resembling those of Alzheimer's, studies revealed that deposits of proteins (called "plaques") were recognized and degraded more quickly. The notorious plaques are among the hallmarks of Alzheimer's disease, and are suspected to cause neuronal damage.
The research focuses on TREM2, a so-called receptor on the cell surface to which other molecules can attach. TREM2 can occur in different versions from person to person - some of these altered versions drastically increase the risk of developing Alzheimer's in old age. In previous studies, researchers found that these special variants put the microglia into an irreversible dormant state, which prevents the immune cells from functioning properly to recognize, absorb and break down plaques and dead cells. "Conversely, we suspect that activation of the microglia could help to eliminate plaques and thus combat Alzheimer's. TREM2 seems to play an important role in this process. The receptor apparently helps to switch the microglia from dormant to active mode."
This is precisely the approach the team are pursuing. The antibody identified, which is now generated using biotechnological methods, binds to TREM2, thereby triggering processes that enhance microglia activity. However, the researchers cautioned that further studies are required prior to progressing this approach to clinical trials: "We have shown that immune cells can be stimulated to break down amyloid deposits more effectively. This demonstrates that our approach can work in principle. However, there is still a long way to go before it can be tested in humans and additional data is necessary to validate this approach."
Link: https://www.dzne.de/en/news/press-releases/press/immune-cells-against-alzheimers/