Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells. These abnormally configured proteins are thought to play a central role in Alzheimer’s disease (AD). Most therapies designed to treat AD target these plaques, but have failed in clinical trials. Now, new research by Salk scientists may explain why some trials and treatments have been unsuccessful.
Many studies report microglia inhibit the growth of plaques by phagocytosis; however, new research shows that microglia promote the formation of dense-core plaques, and that these plaques play a protective role. The study, “Microglia use TAM receptors to detect and engulf amyloid β plaques,” was published in Nature Immunology.
“Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally,” wrote the researchers. “We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque–associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine.”
There are many types of plaques, 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).
“We show that dense-core plaques don’t form spontaneously. We believe they’re built by microglia as a defense mechanism, so they may be best left alone,” explained Greg Lemke, PhD, a professor in Salk’s Molecular Neurobiology Laboratory. “There are various efforts to get the FDA to approve antibodies whose main clinical effect is reducing dense-core plaque formation, but we make the argument that breaking up the plaque may be doing more damage.”
A previous discovery by the Lemke lab in 2016, demonstrated 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 current research demonstrates that it’s not only dead cells that exhibit the “eat-me” signal and Gas6, but also 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.
The researchers made the discovery using live imaging. They observed 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 suggest that this is beneficial.
“Our research seems to show that when there are fewer dense-core plaques, there seem to be more detrimental effects,” said Youtong Huang, doctoral student and first author on the paper. “With more-diffuse plaques, there’s an abundance of dystrophic neurites, a proxy for neuronal damage. I don’t think there’s a distinct clinical decision on which form of plaque is more or less detrimental, but through our research, we seem to find that dense-core plaques are a bit more benign.”
Their findings open a new path of developing a treatment for Alzheimer’s disease and may lead to new studies with this discovery. The researchers would like to conduct cognitive studies to see if increasing the activity of microglial TAM receptors would alleviate the effects of AD.
Lemke noted, “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 scientists suggest that researchers should stop focusing 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 the transport of amyloid-beta out of the brain altogether.