In a study published today in Nature Neuroscience, a group of researchers led by Takaomi Saido of the RIKEN Brain Science Institute in Japan have reported the creation of two new mouse models of Alzheimer’s disease that may potentially revolutionize research into this disease.
Alzheimer’s disease, the primary cause of dementia in the elderly, imposes a tremendous social and economic burden on modern society. In Japan, the burden of the disease in 2050 is estimated to be a half a trillion US dollars, a figure equivalent to the government’s annual revenues.
Unfortunately, it has proven very difficult to develop drugs capable of ameliorating the disease. After a tremendous burst of progress in the 1990s, the pace of discoveries has slowed. Dr. Saido believes that part of the difficulty is the inadequacy of current mouse models to replicate the real conditions of Alzheimer’s disease and allow an understanding of the underlying mechanisms that lead to neurodegeneration. In fact, much of the research in Alzheimer’s disease over the past decade may be flawed, as it was based on unrealistic models.
The problem with older mouse models is that they overexpress a protein called amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer’s disease. However, in mice the overexpression of APP gives rise to effects which are not seen in human Alzheimer’s disease.
For example, the APP mutant mice often die of unknown causes at a young age, and the group believes this may be related to the generation of toxic fragments of APP, such as CTF-beta. In addition, some of the fragments of APP could be neuroprotective, making it difficult to judge whether drugs are being effective due to their effect on Abeta peptides, which are known to be involved in human AD, or whether it is due to other effects that would not be seen in human disease. In addition, the gene for expressing APP is inserted in different places in the genome, and may knock out other genes, creating artifacts that are not seen in humans.
With this awareness, more than a decade ago Dr. Saido launched a project to develop a new mouse model that would allow more accurate evaluation of therapies for the disease. One of the major hurdles involved a part of the gene, intron 16, which they discovered was necessary for creating more specific models.
The first mice model they developed (NL-F/NL-F) was knocked in with two mutations found in human familial Alzheimer’s disease. The mice showed early accumulation of Abeta peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss.
These new models could help in two major areas. The first model, which expresses high levels of the Abeta peptides, seems to realistically model the human form of AD, and could be used for elucidating the mechanism of Abeta deposition. The second model, which demonstrates AD pathology very early on, could be used to examine factors downstream of Abeta-40 and Abeta-42 deposition, such as tauopathy, which are believed to be involved in the neurodegeneration. These results may eventually contribute to drug development and to the discovery of new biomarkers for Alzheimer’s disease. The group is currently looking at several proteins, using the new models, which have potential to be biomarkers.
According to Dr. Saido, “We have a social responsibility to make Alzheimer’s disease preventable and curable. The generation of appropriate mouse models will be a major breakthrough for understanding the mechanism of the disease, which will lead to the establishment of presymptomatic diagnosis, prevention and treatment of the disease.”
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The brain is a wonderfully flexible and adaptive learning tool. For decades, researchers have known that this flexibility, called plasticity, comes from selective strengthening of well-used synapses — the connections between nerve cells.
Now, researchers at the Stanford University School of Medicine have demonstrated that brain plasticity also comes from another mechanism: activity-dependent changes in the cells that insulate neural fibers and make them more efficient. These cells form a specialized type of insulation called myelin.
“Myelin plasticity is a fascinating concept that may help to explain how the brain adapts in response to experience or training,” said Michelle Monje, MD, PhD, assistant professor of neurology and neurological sciences.
The researchers’ findings are described in a paper published online April 10 in Science Express.
“The findings illustrate a form of neural plasticity based in myelin, and future work on the molecular mechanisms responsible may ultimately shed light on a broad range of neurological and psychiatric diseases,” said Monje, senior author of the paper. The lead authors of the study are Stanford postdoctoral scholar Erin Gibson, PhD, and graduate student David Purger.
Sending neural impulses quickly down a long nerve fiber requires insulation with myelin, which is formed by a cell called an oligodendrocyte that wraps itself around a neuron. Even small changes in the structure of this insulating sheath, such as changes in its thickness, can dramatically affect the speed of neural-impulse conduction. Demyelinating disorders, such as multiple sclerosis, attack these cells and degrade nerve transmission, especially over long distances.
Myelin-insulated nerve fibers make up the “white matter” of the brain, the vast tracts that connect one information-processing area of the brain to another. “If you think of the brain’s infrastructure as a city, the white matter is like the roads, highways and freeways that connect one place to another,” Monje said.
In the study, Monje and her colleagues showed that nerve activity prompts oligodendrocyte precursor cell proliferation and differentiation into myelin-forming oligodendrocytes. Neuronal activity also causes an increase in the thickness of the myelin sheaths within the active neural circuit, making signal transmission along the neural fiber more efficient. It’s much like a system for improving traffic flow along roadways that are heavily used, Monje said. And as with a transportation system, improving the routes that are most productive makes the whole system more efficient.
In recent years, researchers have seen clues that nerve cell activity could promote the growth of myelin insulation. There have been studies that showed a correlation between experience and myelin dynamics, and studies of isolated cells in a dish suggesting a relationship between neuronal activity and myelination. But there has been no way to show that neuronal activity directly causes myelin changes in an intact brain. “You can’t really implant an electrode in the brain to answer this question because the resulting injury changes the behavior of the cells,” Monje said.
The solution was a relatively new and radical technique called optogenetics. Scientists insert genes for a light-sensitive ion channel into a specific group of neurons. Those neurons can be made to fire when exposed to particular wavelengths of light. In the study, Monje and her colleagues used mice with light-sensitive ion channels in an area of their brains that controls movement. The scientists could then turn on and off certain movement behaviors in the mice by turning on and off the light. Because the light diffuses from a source placed at the surface of the brain down to the neurons being studied, there was no need to insert a probe directly next to the neurons, which would have created an injury.
By directly stimulating the neurons with light, the researchers were able to show it was the activation of the neurons that prompted the myelin-forming cells to respond.
Further research could reveal exactly how activity promotes oligodendrocyte-precursor-cell proliferation and maturation, as well as dynamic changes in myelin. Such a molecular understanding could help researchers develop therapeutic strategies that promote myelin repair in diseases in which myelin is degraded, such as multiple sclerosis, the leukodystrophies and spinal cord injury.
“Conversely, when growth of these cells is dysregulated, how does that contribute to disease?” Monje said. One particular area of interest for her is a childhood brain cancer called diffuse intrinsic pontine glioma. The cancer, which usually strikes children between 5 and 9 years old and is inevitably fatal, occurs when the brain myelination that normally takes place as kids become more physically coordinated goes awry, and the brain cells grow out of control.