Alzheimer’s disease is characterized by the buildup of amyloid-beta proteins in the brain. Experts believe that these proteins occur naturally in healthy brains, but when our bodies stop being able to clear them out properly, they collect and form plaques that interrupt the connection between neurons in the brain.
Most Alzheimer’s therapies are designed to help target these plaques, but they’ve mostly failed in clinical trials. But new research is indicating that there’s an underlying reason why these treatments have not been successful.
There are two main types of plaques in the brain: dense-core plaques and diffuse plaques. Dense-core plaques have a compact center surrounded by a halo of looser proteins. Diffuse plaques are wispier, loosely organized in clouds.
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The belief, until now, has been that the body clears out plaques in the brain by sending trash-clearing immune cells, called microglia, to “eat” the plaques. Salk researchers, however, have recently discovered that microglia may actually promote the formation of the dense-core plaques as a protective measure against diffuse plaques, keeping them from getting to neurons, where they can cause cell death.
“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. “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.”
The researchers believe microglia use diffuse amyloid-beta fibrils to form dense-core plaques as part of their cellular cleanup process. They do “eat” the more diffuse plaques, along with other dead cells that put out an “eat me” signal when they die, but they process these cells into a compact aggregate that becomes a dense-core plaque. This is probably even a beneficial process, because it organizes diffuse plaques into a more compact space and clears debris from the intercellular environment.
“Our research seems to show that when there are fewer dense-core plaques, there seem to be more detrimental effects,” says Youtong Huang, 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.”
These findings demonstrate that developing new methods of treating Alzheimer’s will be necessary, such as boosting the expression of TAM receptors on microglia to help accelerate the clearing of diffuse plaques and the formation of dense-core plaques. Other treatments might be able to reduce the production of amyloid-beta in the first place or facilitate the transport of amyloid-beta out of the brain.
The researchers’ work was published in the journal Nature Immunology. Next, they hope to conduct cognitive studies to see if increased microglial TAM receptors alleviate the effects of Alzheimer’s disease.Whizzco