Web Date: December 9, 2015
Small Molecule Breaks Up Amyloid Aggregates In Mice
Although the hypothesis has become increasingly contentious, many scientists still believe that amyloid-β peptides play a key role in triggering Alzheimer’s disease when they clump together in oligomers and plaques in the brain. Much effort and research funding has been poured into developing treatments such as monoclonal antibodies that prevent these clumps from forming or break them up after they’ve formed.
Now, researchers led by YoungSoo Kim from the Korea Institute of Science & Technology have found that a small molecule called 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) breaks up amyloid clumps in the brains of mice and relieves the rodents of some Alzheimer’s-like symptoms (Nat. Commun. 2015, DOI: 10.1038/ncomms9997). If this molecule—a commercially available compound used by biologists to adjust the pH of buffer solutions—eventually proves effective in human Alzheimer’s patients, it would be easier to synthesize and therefore less expensive than antibodies currently being administered in clinical trials.
The team discovered EPPS’s ability to break up amyloid clumps through a cell-based assay. To test its ability to reduce amyloid-β aggregates and Alzheimer’s-like symptoms in mice, the researchers used rodents engineered to express two common human genes for the disease. The team established that these mice were steadily showing signs of cognitive deficits in memory and learning tasks such as swimming through mazes. Then the researchers administered various daily doses of EPPS up to 30 mg/kg in the rodents’ drinking water for three months. When they repeated the original learning and memory challenges, the researchers found that mice treated with EPPS showed improved performance—almost to the level of normal mice—and that untreated mice showed a deterioration in performance.
At the end of the testing period, the researchers sacrificed the mice and used stains to analyze the presence of amyloid in their brains. EPPS-treated mice showed a significant decrease in amyloid-β plaques: Rodents given the maximal 30-mg/kg dose had virtually no plaques in their hippocampi, whereas untreated mice showed a twofold increase in the number of plaques in their hippocampi.
Several experimental treatments that have moved from preclinical testing into clinical trials for Alzheimer’s disease have been able to stop the formation of new amyloid-β aggregates in animal models or break up aggregates that have already formed. However, some argue breaking up these aggregates may not be the right approach because of a certain side effect: Some therapeutic hopefuls have broken up amyloid plaques but generated smaller oligomeric aggregates that actually accelerated cognitive decline in some patients, says Samuel Gandy, chair of Alzheimer’s disease research at Mount Sinai Hospital, who was not involved in the study. Still, Gandy says, clearing amyloid from the brain is probably desirable in treating Alzheimer’s. If scientists could guarantee that a therapeutic does not eventually lead to more toxic oligomers, an agent with disaggregation properties would be “a good thing,” he adds.
Although Kim was encouraged to see that his group’s disaggregating compound seemed to restore cognitive abilities to mice, he says such a dramatic result will probably not translate to human patients. “Mice have a different biology than humans in Alzheimer models,” says Kim, explaining that human brain cells tend to remain damaged even after amyloid-β plaques clear, making cognitive improvements unlikely.
But that doesn’t mean EPPS would be useless, Kim contends. Scientists are currently testing brain scan methods that might one day allow doctors to see amyloid-β accumulating in live patients’ brains. In the future, diagnostics such as this could identify patients at a high risk of Alzheimer’s disease before their symptoms develop, he says. For these patients, therapies like EPPS could prevent or break up amyloid-β aggregates before they cause irreversible damage. Kim’s group is currently looking for an industrial partner to implement further preclinical and clinical trials for the compound.
- Chemical & Engineering News
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