One of the hallmarks of Alzheimer’s disease (AD) is the buildup of amyloid-beta plaques in the brain. Most therapies designed to treat AD target these plaques, but they have largely failed in clinical trials. New research from Salk scientists upsets conventional views on the origin of a prevalent type of plaque, pointing to a reason treatments have failed.
The traditional view holds that immune cells in the brain, called microglia, inhibit the growth of plaques by “eating” them. Instead, Salk scientists show that microglia promote the formation of dense-core plaques and that this action sweeps the wispy plaque material away from neurons, where it causes cell death. The research, which was published in Nature’s immunology on April 15, 2021, suggests that dense-core plaques play a protective role, so treatments to destroy them may do more harm than good.
“We show that dense-core plaques do not form spontaneously. We believe that they are built by the microglia as a defense mechanism, so it is best to leave them alone,” says Greg Lemke, professor at the Molecular Neurobiology Laboratory at Salk. “There are various efforts to get the FDA to approve antibodies whose primary clinical effect is to reduce the formation of dense-core plaques, but we argue that rupturing the plaque may cause more damage.”
Alzheimer’s disease is a neurological disease that causes memory loss, disturbances in thinking and changes in behavior, which get worse with age. The disease appears to be caused by abnormal proteins that aggregate between brain cells to form the characteristic plaques, which disrupt the activity that keeps cells alive.
There are many forms of plaque, but the two most common are characterized as “diffuse” and “dense core”. Diffuse plates are loosely organized amorphous clouds. Dense-core plates have a compact center surrounded by a halo. Scientists have generally believed that both types of plaques form spontaneously from excessive production of a precursor molecule called amyloid precursor protein (APP).
But, according to the new study, it’s actually microglia that form dense-core plaques from diffuse amyloid-beta fibrils, as part of their cellular cleansing.
This builds on a discovery from the Lemke lab in 2016, which determined that when a brain cell dies, a fatty molecule turns from the inside to the outside of the cell, signaling, “I’m dead, eat- me”. The microglia, via surface proteins called TAM receptors, then engulf, or “eat” the dead cell, using an intermediate molecule called Gas6. Without TAM and Gas6 receptors, microglia cannot connect to and consume dead cells.
The team’s current work shows that it’s not just dead cells that present the Eat-Me and Gas6 signal: the same is true of amyloid plaques that are prevalent in Alzheimer’s disease. Using animal models, the researchers were able to demonstrate experimentally for the first time that microglia with TAM receptors eats amyloid plaques via the eat-me and Gas6 signal. In mice designed not to have TAM receptors, the microglia were unable to perform this function.
Digging deeper, they tracked down the dense-core plaques using live imaging. To their surprise, the team found that after a microglial cell ate a diffuse plaque, it transfers engulfed amyloid-beta into a highly acidic compartment and converts it into a highly compacted aggregate which is then transferred to a dense core plate. The researchers propose that this is a beneficial mechanism, organizing the diffusion into dense-core plaque and removing the intercellular environment of the debris.
“Our research seems to show that when there are fewer dense-core plaques, there seem to be more adverse effects,” says Youtong Huang, the paper’s first author. “With more diffuse plaques, there is an abundance of dystrophic neurites, an indicator of neuronal damage. I don’t think there is a separate clinical decision on which plaque shape is more or less detrimental, but thanks to our research, we seem to find that the dense-core plaques are a bit more benign. “
Their findings suggest new ways to develop a treatment for Alzheimer’s disease, such as increasing the expression of TAM receptors on microglia to accelerate the formation of dense-core plaques. The team would like to conduct cognitive studies to see if increased activity of TAM microglial receptors would lessen the effects of AD.
Lemke, who holds the Françoise Gilot-Salk Chair, believes the current failure rate of most Alzheimer’s drug trials is about to end. “Some people say that the relative failure of tests that destroy dense-core plaques disproves the idea that beta-amyloid is a bad thing in the brain,” Lemke says. “But we are arguing that beta-amyloid is still clearly a bad thing; it’s just that you have to ask yourself if dense core plaques are a bad thing.”
Lemke suggests scientists looking for a cure for Alzheimer’s disease should stop trying to focus on rupturing dense-core plaques and start looking for treatments that reduce the production of amyloid-beta by first place or therapies that facilitate the transport of amyloid-beta. of the brain in total.