Microglia Need Helpers
The researchers also discovered the signal comes via receptors called Axl and Mer, which are part of a larger family of TAM receptors which need the help of a molecule called Gas6. Without TAM receptors and Gas6, microglia won't attach to and eat dead cells, leaving the brain vulnerable to amyloid build up and Alzheimer's disease. Although the scientists had theorized that TAM had a potential role in Alzheimer's disease, they needed to know more. In particular researchers were interested in what happens to diffuse and dense-core plaques, the two most prevalent types of amyloid beta proteins. Diffuse plaques are loosely organized with no defined structure, while dense-core plaques are compact. Both were believed to be formed spontaneously, triggered by a precursor molecule called amyloid precursor protein (APP). So, for their latest research, published in the journal Nature Immunology in April, researchers used two groups of mice with a build-up of amyloid plaque in the brain. One group was free of TAM, and the hypothesis was that they would be unable to clean up cellular debris. Their study showed for the first time that this is indeed the case. Mice with fully functioning microglia engulfed and consumed amyloid plaques via TAM and Gas6 just as they do with dead cells. Mice without TAM were unable to do this. Researchers also discovered something else that came as a real surprise.Creating Plaque as a Protective Mechanism
Researchers had theorized that the TAM-free mice would have a greater build-up of dense-core plaques than mice with TAM. Yet while TAM-free mice did accumulate more plaques in diffuse form, they only had half as many dense-core plaques. Why? Researchers used live imaging to take a closer look and discovered that in order to prevent diffuse plaques from building up and causing cell death, the microglia treat them like a garbage truck that compacts trash, crushing the amyloid and releasing it in dense-core form. So, instead of clearing away these plaques, the microglia actually create them. Senior author Greg Lemke explains how the findings increase his concern over efforts to develop Alzheimer’s drugs to clear amyloid plaques. "...[W]hat the microglia do is they engulf this loose stuff [the diffuse plaque] and they put it in vesicles where they compact it very, very, very tightly. Then, they spit it back out and put it into the dense-core plaques. "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. "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 antibodies have spectacular success at breaking up the plaques [but] they have... quite marginal effects on improving patients' cognitive abilities..." As our long-time readers know, this publication has long been skeptical of the theory that beta amyloid plaque is the cause of Alzheimer’s disease; the failure of plaque-busting drugs is actually old news. We’ve reported that the plaques appear to serve a protective function – they are actually the body’s effort to protect against whatever the real underlying cause of dementia is. Researchers have slowly been moving away from the beta plaque theory for years, although like a cat it seems to have nine lives. Maybe this study will finally put an end to it.What This Discovery Means for Alzheimer’s Treatment
Prof. Lemke isn't saying that dense-core plaques are good for the brain, however he thinks they may be a by-product of the brain trying to "make the best of a bad situation." Prof. Lemke suggests scientists who are trying to find a cure for Alzheimer's focus on treatments that reduce the production of amyloid in the first place, or on treatments that transport amyloid out of the brain altogether, rather than attempting to remove the dense-core amyloid plaques.