Are Some Amyloid Plaques Protective in Old Age and Alzheimer's Disease?
Researchers here provide evidence to suggest that some of the amyloid-β deposits in the brain that are characteristic of Alzheimer's disease are in fact beneficial and protective, the efforts of immune cells to remove harmful amyloid-β from contact with cells and deposit it in elsewhere. This may or may not help to explain why amyloid clearance therapies have so far failed to produce benefits in patients: it is always hard to say just how large a contribution any one given mechanism has to disease progression. It seems likely that amyloid-β aggregates are either a moderately but not severely harmful side-effect of the real core disease processes - such as chronic infection and its consequences - or that amyloid-β aggregation is only relevant in the early stages of Alzheimer's disease. In the later stages of the condition, a feedback loop of inflammation, cellular senescence, and immune system dysfunction drives the condition.
Alzheimer's disease is a neurological condition that results in memory loss, impairment of thinking, and behavioral changes, which worsen as we age. The disease seems to be caused by abnormal proteins aggregating between brain cells to form the hallmark plaques, which interrupt activity that keeps the cells alive. There are numerous forms of plaque, but the two most prevalent are characterized as "diffuse" and "dense-core." Diffuse plaques are loosely organized, amorphous clouds. Dense-core plaques have a compact center surrounded by a halo. Scientists have generally believed that both types of plaque form spontaneously from excess production of a precursor molecule called amyloid precursor protein (APP).
But, according to a new study, it is actually microglia that form dense-core plaques from diffuse amyloid-beta fibrils, as part of their cellular cleanup. This builds on earlier research showing that when a brain cell dies, a fatty molecule flips from the inside to the outside of the cell, signaling, "I'm dead, eat me." Microglia, via surface proteins called TAM receptors, then engulf, or "eat" the dead cell, with the help of an intermediary molecule called Gas6. Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.
The team's current work shows that it's not only dead cells that exhibit the eat-me signal and Gas6: So do the amyloid plaques prevalent in Alzheimer's disease. Using animal models, the researchers were able to demonstrate experimentally for the first time that microglia with TAM receptors eat amyloid plaques via the eat-me signal and Gas6. In mice engineered to lack TAM receptors, the microglia were unable to perform this function.
Digging deeper, they traced the dense-core plaques using live imaging. Much to their surprise, the team discovered that after a microglial cell eats a diffuse plaque, it transfers the engulfed amyloid-beta to a highly acidic compartment and converts it into a highly compacted aggregate that is then transferred to a dense-core plaque. The researchers propose that this is a beneficial mechanism, organizing diffuse into dense-core plaque and clearing the intercellular environment of debris.
"Some people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain. But we argue that amyloid-beta is still clearly a bad thing; it's just that you've got to ask whether dense-core plaques are a bad thing." The researchers suggest that scientists looking for a cure for Alzheimer's should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.
Wow, that is interesting. Seems like immune system research is really ramping up.