Computer illustration of amyloid plaques amongst neurons. Amyloid plaques are characteristic ... [+]
Amyloid beta protein plaques have been a major target of Alzheimer's disease therapeutics for decades, but these drugs keep failing in clinical trials. A new study offers a potential explanation.
That explanation hinges on the fact that not all amyloid beta plaques are created equal. Some are thin and wispy, and others are aptly named dense-core plaques.
"There was this idea that the [dense-core] plaques form spontaneously," said Greg Lemke, a professor at the Salk Institute for Biological Studies and senior author of the study. But while studying the role of the brain’s immune cells in Alzheimer’s disease, his group found that the dense plaques might be part of the brain's defense mechanism.
Genetic studies have found connections between Alzheimer's disease and genes expressed in the brain's immune cells, called microglia. "The role of microglia is to get rid of things that are not needed in the brain that are toxic," said Carmela Abraham, professor of biochemistry, pharmacology and experimental therapeutics at Boston University School of Medicine. Abraham was not involved in the new research.
Lemke's group began this study to look at the role of microglia in mouse models of Alzheimer's disease, focusing on two important receptors called Axl and Mer. Axl and Mer allow microglia to clear out dying cells in the brain. Previous studies had already shown that Axl and Mer, part of a group of microglial receptors called TAM, might have some role in Alzheimer's disease, but the precise role wasn't clear. To figure that out, the researchers compared two groups of mice with amyloid buildup in the brain: one group with functional microglia and one group without microglial TAM receptors.
When the researchers began this study, they thought that mice without TAM receptors would have more dense-core plaque accumulation than mice with fully-functioning microglia. That’s because scientists have thought that microglia restrains the growth of amyloid beta plaques by engulfing the material.
"But surprisingly, we found that these TAM-deficient Alzheimer's disease mice actually develop much fewer dense-core plaques in their cortex and hippocampus," said Youtong Huang, lead author of the study and postdoctoral researcher at the Salk Institute for Biological Studies. The hippocampus is a brain structure important for memory, and the cortex refers to the outer layer of the brain, important for functions like cognition and processing sensory information.
When Huang first showed Lemke her data, he was puzzled. "This doesn't make any sense at all," he thought. In the TAM-deficient mice, removing those receptors prevented microglia from eating up cellular debris, a process called phagocytosis. But instead of having more dense-core plaques, the TAM-deficient mice had half as many. If microglia clear away dense-core plaques in the brain, those results wouldn't make sense.
"But then when we actually see what's going on, it leads to this model, which is inconclusive, that the microglia are building the plaques through phagocytosis," said Lemke. Instead of clearing away the plaques, microglia are creating them. The idea is that microglia could be consuming more harmful forms of amyloid beta buildup and, like a trash compactor, crushing that amyloid beta and releasing it in a compressed form, the dense-core plaques.
By packing away amyloid beta in these dense plaques, microglia might minimize the harm more toxic forms of amyloid beta could cause. Abraham thinks this model makes sense. It supports the pre-existing idea that the dense-core plaques might be less harmful than other forms of amyloid beta.
And it turned out that while the TAM-deficient mice didn't have many dense-core plaques, they did have more plaques in a diffuse form. These loosely packed, "cloud-like" plaques, Lemke said, do form spontaneously, unlike the dense-core plaques. "And what microglia do is they engulf this loose stuff 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," he said.
In the TAM-deficient mice, the researchers also saw more amyloid beta accumulate in and around blood vessels, which could indicate a condition common in Alzheimer's disease, cerebral amyloid angiopathy (CAA). This finding lines up with previous studies that showed increased CAA when microglia were decreased in mice.
Lemke, Huang and their colleagues also examined post-mortem brain tissue from three humans with and three without advanced Alzheimer's disease. They found evidence that the TAM receptors might play a similar role in humans with Alzheimer’s. Still, their experimental model only applies to mice so far.
"It doesn't bring us to treatment right away," said Abraham. Targeting these microglial receptors is complicated, and scientists would need to figure out what effects manipulating those receptors could have on the human brain. "We don't want to shake this very gentle, sensitive balance of receptors," she added.
Another limitation is that their mouse models only reflect one hallmark of Alzheimer's disease, amyloid beta plaques, not the other hallmark, the neurofibrillary tangles of tau protein within cells. "This is another aspect we're interested in, the role of TAM receptors and microglia in tau pathology," said Huang. "That's an incomplete part of the study."
The study, published in Nature Immunology, could, however, explain the failure of some Alzheimer's therapies, like antibodies designed to target dense-core amyloid beta plaques. "The antibodies have spectacular success at breaking up the plaques," said Lemke. But that doesn't translate to symptom improvement. "They have really, in general, quite marginal effects on improving patients' cognitive abilities over six months to a year of treatment."
Abraham said that this might be because, according to Lemke's and Huang's study, "when these antibodies lead to the disaggregation of the plaques, they release from the plaques the more toxic form of amyloid beta."
But this isn’t to say that dense-core plaques are good for the brain, Lemke cautioned. "The dense-core plaques that you see in Alzheimer's disease may be the body's attempt to make the best of a bad situation."
