Two studies from the Washington University School of Medicine in St. Louis, Missouri, reveal new insights into amyloid-β — the plaque-forming protein scientists believe is at the root of Alzheimer’s disease. Both studies homed in on the removal of amyloid-β from the brain, a process thought to be defective in Alzheimer’s patients, offering up new clues on how to prevent the protein from aggregating in the brain.
Scientists have never been able to ascribe a function to the amyloid-β protein, and most people believe that it is released from brain cells as a byproduct of normal brain activity. Although alternative theories have emerged during recent years depicting amyloid-β as an antimicrobial factor crucial for our immune defense against infections, a defective removal of the protein from the brain might lie behind its accumulation in the brain, a phenomenon scientists believe leads to Alzheimer’s disease.
Measuring changes of amyloid-β in the brain allows researchers to explore the effects of drugs intended to lower brain levels of the protein, but until now, available methods have been crude, allowing measurements within a one-hour window.
“For the last 14 years we had a technique in which we would do something to the mouse – give it a drug, have it perform a certain behavior – and we’d find out what happened to its amyloid beta levels an hour later,” said John Cirrito, senior author of one of the studies. “Waiting that long just wasn’t good enough. Neural activity happens on a rapid time scale, and we needed to see a direct connection between the intervention and the amyloid beta levels.”
A new technique developed by Cirrito, an associate professor of neurology at Washington University, and his colleagues, instead measures levels of amyloid-β minute-by-minute, relying on the ability of the protein to create a small amount of electrical current when exposed to a weak electrical signal, a process they describe in a report titled “Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model,” published in the Journal of Experimental Medicine.
The method in itself is not new, but the research team has now downsized and refined it to suit the needs of Alzheimer’s researchers, often studying mouse brains.
“People have used this approach for other molecules, but the detectors were the size of a microscope slide,” Cirrito said. “We adapted it into a five-micron fiber, which is way thinner than a human hair, so it could be implanted into the brain.”
Testing the technique in mice, the research team stumbled across a surprising find, contradicting the team’s earlier research. They realized that there are two pathways involved in the removal of amyloid-β, depending on the concentrations of the protein in the brain. One pathway kicks in when levels are high, but once the levels drop to a certain level, the other clearance pathway starts doing the job. Earlier, they had believed that the concentration did not affect which removal pathway was active.
“This is important if you’re devising a therapeutic strategy against Alzheimer’s disease,” Cirrito said. “If you hit the first pathway, you might have an effect quickly, but you may not be able to lower amyloid beta levels beyond a certain point. You’d have to consider targeting multiple pathways.”
The other study started out with an entirely different perspective, yet the implications of the two studies occupy the same research sphere. Published in the same journal, the study explored why people carrying a mutation in a gene called TREM2 are about five times as likely to develop Alzheimer’s disease.
The TREM2 gene produces a protein that only exists on the surfaces of a brain cell type called microglia, known for being the cleaning staff of the brain.
“We found that microglia without TREM2 behaved abnormally,” said co-senior author Marco Colonna. “We speculate that in Alzheimer’s patients, over time, microglia fail to contain the accumulation of amyloid beta, which causes increasing damage to their brains.”
TREM2, it turned out, is a sensor detecting a molecule present in cell debris, pathogens, or stray proteins, activating microglia for the cleaning task. When the protein is dysfunctional, microglia no longer detects the piles of waste waiting for removal.
The research team removed the TREM2 gene in a mouse engineered to develop extensive amyloid plaques, discovering that the plaques spread out throughout the brain, no longer surrounded by microglia trying to contain them. The report, “TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques,” also describes how the microglia were scattered in these mouse brains, no longer finding the molecules they were supposed to clear.
Although the total amount of amyloid beta in these mice was not different from other mice, their spread seemed to cause more neuronal damage. “If you don’t have TREM2, the plaque spreads into the brain and destroys key parts of the neurons,” Colonna said.
The findings would allow scientists to develop drugs targeting TREM2, or other factors contributing to the signal it sends to microglia, making the cells more effective.
“You could target not just TREM2 but any molecule in the TREM2 pathway to make microglia more active,” Colonna said. “Or you could block any step in the inhibitory pathway.”