Some Alzheimer’s plaques in the brain may be helpful, not destructive, surprising study reveals

LA JOLLA, Calif. — The buildup of amyloid-beta plaques in the brain is one of the main culprits scientists believe triggers Alzheimer’s disease. For decades, researchers have focused on developing dementia treatments that target and destroy these plaques. Unfortunately, the vast majority of these projects fail during the clinical trial stage. Now, a new study is revealing why so many potential treatments fall flat while also changing how scientists view these proteins. Researchers at the Salk Institute say some of those amyloid-beta plaques may not be so bad after all. They add some appear to act in a defensive manner against Alzheimer’s, offering protection for the brain and better cognitive health.

The study finds there are two varieties of plaque in the brains of Alzheimer’s patients: diffuse and dense-core. Diffuse plaques are widely-spaced, amorphous clouds. Dense-core plaques, meanwhile, feature a compact center with a halo surrounding it. Most scientists believe both varieties appear in the brain spontaneously due to excess production of a precursor molecule called amyloid precursor protein (APP).

However, this new research finds microglia, the brain’s “trash-clearing immune cells,” are responsible for dense-core plaques, creating them as part of their “cellular cleanup” duties.

How do plaques help clean up the brain?

For a long time, the accepted medical view was that microglia actively work against the proliferation of these plaques by “eating” them. This new set of research throws a big wrench into that theory. Researchers report microglia actually promote the formation of dense-core plaques. This action, the study states, moves wispy plaque material away from neurons. This is a positive because if that plaque material remains close to neurons it would induce cell death.

With these new discoveries in mind, the team at SI speculate dense-core plaques play a protective role in cognition after all. This would explain why so many prior treatments designed to destroy them have largely done more harm than good.

“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,” says Greg Lemke, a professor in Salk’s Molecular Neurobiology Laboratory, in a media release. “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.”

In 2016, Lemke’s team discovered that whenever a brain cell dies, it lets out a signal essentially saying “I’m dead, eat me.” Microglia hear that message and eat the dead cell via TAM receptors and an intermediary molecule called Gas6. This more recent research shows it isn’t just dead cells that send out that message. The amyloid plaques connected to Alzheimer’s do as well.

Changing the way scientists look at Alzheimer’s treatments

Next, researchers used animal models to confirm for the first time ever that microglia with TAM receptors consume amyloid plaques thanks to the “eat-me” signal and Gas6.

While using live-imaging to track dense-core plaques, the research team was surprised to find that whenever a microglial cell eats a diffuse plaque the consumed amyloid-beta is sent to a highly acidic compartment. The plaque is then changed into a highly compacted aggregate that is ultimately moved to a dense-core plaque.

Study authors suspect this is a beneficial process for the mind, which organizes diffuse plaques into dense-core plaques and clears away neural debris.

“Our research seems to show that when there are fewer dense-core plaques, there seem to be more detrimental effects,” comments first study author Youtong Huang. “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.”

These findings change a whole lot when it comes to Alzheimer’s research. First off, this opens the door for numerous new potential treatment avenues, such as something that would boost the expression of TAM receptors on microglia, accelerating dense-core plaque formation.

“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,” Lemke concludes. “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 study appears in the journal Nature Immunology.

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