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Freedom for oligomers

New model for Alzheimer’s reproduces in monkeys the alterations the disease causes in the human brain

Tangles of tau protein (in green): common in the advanced stages of Alzheimer's and now reproduced in the brains of monkeys

LETICIA FORNY-GERMANO / UFRJTangles of tau protein (in green): common in the advanced stages of Alzheimer’s and now reproduced in the brains of monkeysLETICIA FORNY-GERMANO / UFRJ

Researchers were in for a surprise when they injected into the brains of monkeys a substance associated with the origin of Alzheimer’s disease in humans. The molecules migrated and accumulated in areas related to memory formation, producing alterations in the cells that are typical of the advanced stages of this disease. This finding, which is important to understanding how the disease works, alerts us to the need to use primates as a model for understanding how Alzheimer’s develops and for testing possible treatments, according to Dr. Fernanda de Felice of the Federal University of Rio de Janeiro (UFRJ), neuroscientist and coordinator of the research.

In partnership with the Canadian group at Queen’s University led by neurophysiologist Douglas Muñoz, Dr. de Felice and her team wanted to know how the disease develops in a healthy brain. So they injected small fragments (oligomers) of the beta-amyloid protein, precursors of cellular damage, into the lateral ventricle—one of natural cavities of the brain that produces the cerebrospinal fluid that bathes the brain—of the animal’s brain. The idea was not to determine a location to insert the substance. “We wanted to free the oligomers,” she said.

The researchers found that in both rats and cynomolgus monkeys (Macaca fascicularis) the oligomers accumulate in the frontal cortex, hippocampus and areas associated with memory and cognitive aspects, according to an article published in the October 2014 issue of the Journal of Neuroscience, whose lead author is Leticia Forny-Germain, a biologist of the UFRJ group. “The first areas affected in the disease reflect what happens in humans,” says Dr. de Felice.

Earlier experiments done on cells and rodents have suggested that beta-amyloid oligomers play a central role in the development of the disease, causing irreversible memory loss and dementia (see Pesquisa FAPESP Issue No. 194). It has been impossible to obtain this causal relationship in an experimental model approaching the complexity of the human brain, and so far no one has managed to reproduce the damage that Alzheimer’s causes in people in the brains of primates.

The most important aspect of the experiment, according to Dr. de Felice, was to observe damage in the monkeys similar to that occurring in the human brain, such as loss of connections (synapses) between brain cells and alterations in tau protein, responsible for microtubule structures that stabilize extensions of neurons. Altered tau proteins formed neurofibrillary tangles, a typical change in advanced stages of the disease. The neurofibrillary tangles, which are common in the human brain and now observed in the monkeys did not occur in the brains of rodents, usually used as models for the study of Alzheimer’s disease. “There are no studies showing the appearance of tangles solely due to the action of oligomers in rodents,” says Dr. de Felice. “Now, without mutations, we were able to induce a condition that is central to the disease.”

Beta-amyloid oligomers (in red): clustered around neurons in the cerebral cortex of cynomolgus monkeys

LETICIA FORNY-GERMANO / UFRJBeta-amyloid oligomers (in red): clustered around neurons in the cerebral cortex of cynomolgus monkeysLETICIA FORNY-GERMANO / UFRJ

Tau and beta
Alterations in tau protein caused by beta-amyloid protein were also the focus of a study led by Rudolph Tanzi and Doo Yeon Kim of the Harvard Medical School, which was also published in October 2014 in the journal Nature. “Beta-amyloid indeed causes the tangles, which has not been shown before.” Tanzi said in the Nature podcast. The difference in this case was placing human neurons with mutations typical of the hereditary form of Alzheimer’s in a three-dimensional gelatinous matrix instead of the traditional cell culture in a liquid medium on plates where the cells are arranged in a single layer. They hope to use the three-dimensional model to test drugs with the potential to combat the disease in its early stages, before symptoms appear. One of the advantages of using isolated cells, they say, is the ability to closely follow the action of the drug candidate compounds and identify whether they act on the production and arrangement of the beta-amyloid or on formation of the tangles. “We were able to dissect these two events,” says Tanzi. He believes that the model will be able to test drugs 10 times faster, at perhaps a tenth of the cost of tests on rodents.

For Dr. de Felice, these results do not diminish the importance of using primates in studies of Alzheimer’s. “The in vitro model allows you to test the action of various neuroprotective substances, but it is not a complex system like the brain,” she says, arguing that the gelatinous matrix does not include all the cell types at work in the brain. Moreover, she notes, there are no models for the most common form of Alzheimer’s disease, known as sporadic. “They used the mutations described for the familial form, which represents less than 5% of cases of the disease.”

Dr. de Felice plans to continue the experiments with rats and mice to better understand the process by which the disease changes the brain. But she believes that rodents will not help in certain aspects of the research. “Most of the drugs tested in mice are not effective in treating diseases of the human brain,” she says.

The model developed by the team from the Federal University of Rio de Janeiro and Canada was highlighted in the specialized forum known as Alzforum and in comments in the journal Nature, but it is not complete. For example, it has not shown that oligomers impair memory in mice. At Queen’s University in Canada, some monkeys have already begun to be trained for phase 2 of the studies, in which the researchers will assess behavioral changes that may arise as a result of injecting oligomers. Cynomolgus monkeys must be trained for six months to perform memory tests, such as recognizing images on a monitor, and to move their eyes in a certain way. As the monkeys age, their ability to perform this movement deteriorates in a fashion similar to what occurs in people with Alzheimer’s.

Dr. de Felice also hopes to test drugs in primates. The first candidate is a treatment for diabetes, which her group showed was able to block certain neuronal damage seen in animal models of Alzheimer’s (see Pesquisa FAPESP Issue No. 215). In addition to the promising results of establishing a new animal model, she is celebrating the partnership with the Canadian laboratory. “We are two groups that have complementary expertise,” she says. This is a recipe for success and significant advances in science.

Scientific articles
FORNY-GERMANO, L. et al. Alzheimer’s disease-like pathology induced by amyloid-oligomers in nonhuman primates. Journal of Neuroscience. v. 34, n. 41. 8 Oct. 2014.
CHOI, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. on-line. 12 Oct. 2014.