Drug companies have spent billions of dollars searching for therapy to turn or significantly slow Alzheimer's disease without success. Some researchers argue that the best way to achieve progress is to create better animal models for research, and several teams are now developing mice that simulate more closely how the disease destroys the brain of humans.
The US National Institute of Health (NIH), the UK Institute of Dementia Research and the Jackson Laboratory (JAX) – one of the largest suppliers of laboratory mice in the world, are among the groups that are trying to generate more sophisticated rodents. Scientists are also researching a complex network of mutations that affect neurological decline in mice and humans.
"We appreciate that the models we had were insufficient," says Bruce Lamb, a Indiana Indiana neurologist at Indianapolis, who runs the NIH-funded program. "I think it is right now at a critical moment."
Alzheimer's disease is marked by cognitive impairment and by the development of amyloid-protein plaques in the human brain, but the disease does not occur naturally in mice. Scientists include this by studying mice that have been genetically modified to produce high levels of human amyloid protein. These mice develop plaques in the brain, but they still do not show the memory problems seen in humans.
Many experimental drugs that successfully removed plaque from the mice brain did not reduce the symptoms of Alzheimer's disease in humans. A high profile appeared last month, when three companies reported that their drugs on Alzheimer's disease – a class called BASE inhibitors – failed in major clinical trials at a late stage. Although the drugs successfully blocked the accumulation of amyloid proteins in mice, they seemed to exacerbate the cognitive decline and brain reduction in humans.
Complex genetic stew
The device for better mice models comes as research on genetics links the most common form of Alzheimer's disease – late at the beginning – to dozens of different genes1. This diversity suggests that every case of the disease is caused by a different combination of genetic and environmental factors. "There is no single Alzheimer's disease," said Garret Howell, a neurologist at the Jackson Laboratory (JAX) in Bar Harbor, Maine.
Howell argues that scientists' reliance on laboratory mice with only a few genetically engineered mutations can be limited in research. His work suggests that in mice, as in humans, genetic diversity plays a role in determining how neurodegeneration progresses.
When Howell's team modified both genes associated with Alzheimer's disease in laboratory mice and their wild cousins, all animals developed amyloid plaques. But although the more-arrived laboratory mice did not show any external signs of Alzheimer's disease, part of the genetically diverse wild mice experienced memory problems. The researchers believe that the combination of plaques and unknown genetic factors causes these symptoms. They presented results this month at a meeting of the Society for Neuroscience in San Diego, California.
Another study, by neuroscientist Katherine Kachorovsky in JAX, suggests that genetic makeup of animals affects how they react to environmental triggers. Its group cultivates genetically different wild mice of laboratory mice with mutations that cause the formation of amyloid plaques. Some of the offspring are more likely to develop cognitive problems if they eat high-fat diet, but other mice with a diet have a lower risk of these symptoms, Kachorovski told a San Diego meeting.
Processing of rodents
Understanding how this expanded universe of genetic factors affects the risk of Alzheimer's disease will require a host of new animal models with different combinations of mutations. A few efforts to engineer these mice from the new generation are already under way.
In 2016, NIH began with the MODEL-AD consortium to develop more Alzheimer's mice and make them available to researchers. Project scientists engineer mice with different genetic mutations associated with early or late onset of Alzheimer's disease, and animal testing to see if they show signs of the disease. Then publish descriptions of each type of mouse in an online database. The lamb said the team had published about 30 mice and received more than 500 animal orders from academics and biotech companies.
And in January, the British Research Institute for Dementia in London launched a similar program. Scientists develop a model of mice whose brains show amyloid plaques and entangles of another protein called tau, which occurs in people with Alzheimer's disease. To mimic inflammation of the brain that causes the disease, the group implants neural immune cells from human stem cells in the brain of mice.
Ultimately, researchers hope models will discover ways to predict whether a person will respond to a particular Alzheimer's disease. And with a better understanding of how inflammation and genes lead the disease can help identify with humans before plaques and entangles are formed, says Rudolf Tanzi, a Neurologist at Harvard University in Cambridge, Massachusetts. "It is therefore so important to have these models of animals available and really start working on all of these genes."
But Bart de Stroner, a molecular biologist at the Catholic University of Leuven (CU Leuven) in Belgium, calls for caution. De Stropor, who runs the UK program, says that none of the next-generation animals is likely to be a perfect analogue for humans. "The biggest mistake you can make," he says, "is to think you can ever have a mouse with Alzheimer's disease."
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