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Immune cells are reprogrammed in Alzheimer’s brains

No effective therapy for Alzheimer's disease yet exists. However, scientists from the Hertie Institute for Clinical Brain Research at the University of Tübingen are pursuing an innovative treatment approach using immune cells to eliminate the protein deposits that are the hallmark of Alzheimer’s. Dr. Jonas Neher and his team tested whether exchanging brain-specific immune cells with fresh, more active cells has a positive effect on the disease. Although the experiment did not produce the expected result, the researchers are still hoping that an additional stimulus will induce the cells to act against the deposits in the brain.

More than 46 million people around the world suffer from Alzheimer's. Due to the ageing population, it is expected that the number of Alzheimer's patients will start doubling approximately every 20 years. Alzheimer's disease is a neurodegenerative disease characterised by the deposition of insoluble protein plaques (so-called beta amyloid (Aβ)) in the brain. As Alzheimer's progresses, more and more nerve cells die and the brain tissue shrinks. Typical Alzheimer's symptoms include progressive deterioration of memory performance and behavioural problems. The disease almost exclusively affects older people. When it does occur in younger people, this can usually be attributed to inherited alterations. Alzheimer's remains incurable, even though researchers around the world have been working on finding therapies for many years.

Immune cells as therapeutic option

Dr. Jonas Neher is head of the research group Experimental Neuroimmunology at the Hertie Institute for Clinical Brain Research in Tübingen. © University of Tübingen

Dr. Jonas Neher and his team of researchers at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Centre for Neurodegenerative Diseases have been working on neuroimmunological approaches for the treatment of Alzheimer's disease for many years. They are specifically trying to find out whether immune cells can be used to treat the disease. Their work is based on research findings that suggest the following: genetic alterations that affect the immune system increase an individual's risk of developing Alzheimer's, and immune cells become non-functional due to ageing processes in Alzheimer's brains. It seems that although immune cells cluster around the plaques, they are unable to break down protein deposits effectively. "This led us questioning whether one possible therapeutic option would be to replace old immune cells in the brain with new, more active ones," says Neher.

To test their hypothesis, the neuroscientists from Tübingen used genetically modified mice models that showed the major Alzheimer's characteristics: insoluble protein deposits in the brain and immune reactions against these deposits, i.e. the clustering of immune cells around the plaques. The Alzheimer's mice were crossed with mice whose brain-resident immune cells could be specifically destroyed. The Tübingen researchers observed that in the mice whose brain-resident immune cells were destroyed, immune cells automatically started to migrate from the blood into the brain a few weeks after treatment. "The new immune cells spread throughout the brain in a similar way to the old cells. Unexpectedly, the cells did not move towards to the plaques in the first instance. Under the influence of the surrounding tissue, the cells eventually underwent similar changes to their predecessors and started to cluster around the plaques," said Neher. "We had of course been hoping that the new cells from the blood would have positive effects and destroy the plaques. Unfortunately, the pathology in Alzheimer's brains did not improve." The results were not quite what the researchers expected, as simply replacing the immune cells in Alzheimer's brains did not reverse the deposits.*

The environment is key for immune function

Brain slice of an Alzheimer’s disease mouse model, in which the plaques are stained red and the immune cells black. The immune cells have accumulated around the plaques. © University of Tübingen

"While we did not get the results we were hoping for, we now know that the environment in the brain is essential for immune function and plays a key role in immune cell function," says the brain researcher from Tübingen, adding, "we assume that the pathology in the brain of Alzheimer's patients influences the immune cells in a way that means they can no longer function properly. It appears that, rather than just losing their functions, the immune cells are actually reprogrammed in the brain." The same phenomenon was recently observed in internal organs by other groups of researchers: immune cells transplanted from the blood into a diseased organ lost their original characteristics and adapted to the respective tissue.

The scientists are also interested in how inflammations elsewhere in the body might affect the brain. Patient studies have shown that infections might complicate the course of disease: "Immune cells in the brain always react to an infection, even if it occurs elsewhere in the body. As the immune cells in Alzheimer's brains are altered, this must of course have effects." The researchers therefore want to try and alter the immune cells to make them therapeutically effective. Epidemiological patient studies have also shown that Alzheimer's pathology becomes more severe the more infectious events occur in the body throughout the patient's lifetime.

Additional stimulus for immune cells

The next step for the scientists is to try and further stimulate the immune cells. "We are going to test whether cells retain their function and destroy the plaques after receiving additional stimuli," says Neher. This can be done by applying immunostimulatory drugs into the blood. "It is comparable to an Alzheimer's vaccine that is currently being tested. The vaccine consists of an antibody against the amyloid plaques that protects the immune system from Alzheimer's. The vaccine works by stimulating the body's immune system to attack a protein fragment that is a major component of the plaques, which causes the immune cells to destroy the plaques." Neher's colleagues at the Hertie Institute for Clinical Brain Research in Tübingen are involved in clinical studies that assess the effect of immunisations on the reversal of Alzheimer's. The recently presented preliminary results give some reason to be hopeful, but further research is still needed to substantiate the findings.

* Original publication:

Nicholas H. Varvel, Stefan A. Grathwohl, Karoline Degenhardt, Claudia Resch, Andrea Bosch, Mathias Jucker, and Jonas J. Neher: "Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease." Journal of Experimental Medicine. Advance online publication - 12th October 2015: http://jem.rupress.org/content/early/2015/10/06/jem.20150478.full

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