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Microglial cells – the health police of Alzheimer’s

It starts with memory loss and disorientation. Alzheimer’s disease is the most common type of dementia and is characterised by the loss of neurons and synapses in the brain resulting from the aggregation of beta amyloid protein fragments into fibrils and plaques. Prof. Dr. Knut Biber and his team from the Division of Molecular Psychiatry at Freiburg University Medical Center have analysed these plaques in an in vivo-like cell culture system. They found that microglial cells can prevent the formation of beta amyloid plaques for quite a long period of time but eventually lose the ability to do so.

Prof. Dr. Knut Biber studies the cause of beta amyloid plaque formation in Alzheimer’s and is specifically focused on the role of microglial cells. © Prof. Dr. Knut Biber, Freiburg University Medical Center

Approximately 1.2 million people are living with Alzheimer’s disease (AD) in Germany, and even more will be affected in the future. Women are at a greater risk of developing Alzheimer’s than men. Although there is no cure for the disease, some treatments may delay progression or at least temporarily improve symptoms. Studies on the development of medical treatments, for example involving antibodies, have not been successful. Brains of Alzheimer’s patients are characterised by extracellular beta amyloid fragment depositions (plaques), which are the neurological hallmarks of the disease. Opinions on how the plaques form differ considerably, and the mechanism of plaque formation is far from being fully understood. Some researchers believe that so-called seeds initiate plaque formation in a similar way to the crystallisation process. It is assumed that the degradation of amyloid plaques has a positive effect on the course of the disease. All mammalian brains express beta amyloid (Aβ), but its exact function has remained elusive. Alzheimer’s researchers assume that Aβ is involved in information processing and the physiology of the brain. Aβ plaques are also found in healthy seniors, and they do not always cause disease. Prof. Dr. Knut Biber from the Division of Molecular Psychiatry at the Freiburg University Medical Center believes that Aβ plaques are a general ageing phenomenon. “However, there is evidence that these pathological deposits are a sign of the onset of Alzheimer’s disease,” says Biber, adding, “this seems to be the case because there are no documented cases of Alzheimer that do not involve beta amyloid.”

The role of microglial cells

Previous investigations focused particularly on what happens when plaques are present. Biber explains the process that is thought to be involved in Alzheimer’s: “A ring of cytokine-secreting microglial cells forms around the plaques." But what happens before this? “Our data suggest that microglia can prevent the formation of amyloid plaques for a long period of time. They do this by phagocytosing Aβ,” he explains. The microglial cells to which Biber is referring here are cells found only in the central nervous system, where they protect the brain. The peripheral immune defence cannot cross the blood-brain barrier, so the microglial cells are the main (and first) form of active immune defence for recognising and eliminating pathogenic substances in the CNS. They also help damaged nerve cells to regenerate by forming glial scars, thus protecting them against permanent damage. Microglia are the macrophages of the brain, smaller than nerve cells, and have long thin processes that they use to constantly screen their environment. By taking up or phagocytosing cytotoxic substances, they ensure that no waste accumulates in the brain. Microglia are also believed to be involved in the synaptic plasticity of the brain and strengthen or weaken synapses when required.

Loss of protective function

Microscopic image of what an organotypical hippocampal slice culture (OHSC) is like without microglial cells. Many Aβ plaques (green) form in the OHSC tissue within two weeks growing the culture. © Prof. Dr. Knut Biber, Freiburg University Medical Center

The team led by Biber were able to show in vitro that the microglia take up Aβ fragments and then pack them into their lysosomes where they are degraded, thus preventing them from forming plaques. The microglia prevent the development of diseases such as Alzheimer’s by reducing brain myeloid. However, they are powerless against plaques that have already formed. “Once plaques have been formed in the brain, the microglia are unable to reverse the situation,” says Biber.“ It is still unclear why. Several assumptions have been put forward. One assumption is that the cells become dysfunctional as people get older, and stop working. Cellular senescence, the usual term for cellular ageing, has been described in humans. “The cells defragmentise and take on a strange appearance,” says Biber. Neuropathologists have examined various brain stages of Alzheimer’s and found that microglia pathology precedes Alzheimer’s pathology in all cases. In the search for the causes of Alzheimer’s, researchers around the world have not yet been able to induce plaque formation in wild-type mice. This has only worked with genetically modified Alzheimer’s disease mice that produce huge quantities of Aβ in the brain. Biber believes that the reason why the induction of plaque formation did not work in wild-type mice is the microglial cells that prevented the formation of plaques. Biber and his team created a specific in vitro slice culture system with an in vivo-like environment.

Highly valid in vitro model

Microglial cells (red) have taken up (yellow) Aβ fragments (green). in an organotypic hippocampal slice culture. Very little Aβ is found outside the microglia. © Prof. Dr. Knut Biber, Freiburg University Medical Center

To study the role of microglia, the researchers have used an organotypic hippocampal slice culture (OHSC) made of the hippocampus tissue of a young mouse, which is cut in slices and placed on semipermeable membranes. Beneath the membranes is a culture medium that provides the neurons with nutrients. “This is quite a nice system. It maintains many of the characteristics of the in vivo situation, including three-dimensional organisation, neuronal activity and action potentials. The cells communicate with each other,” says Biber. Biber removed the microglial cells from the OHSC to study their function in greater detail. He found that the addition of a toxin led to the death of all the neurons in the culture.

In a different approach, Biber trickled a beta amyloid solution over the hippocampal microglia culture. The cells survived and most of the Aβ was present in the microglial cells. “When we removed the microglia, plaques developed within two weeks after removal,” says Biber. Aβ plaques were then found extracellularly as well as in neurons whose nuclear membrane was damaged. Biber’s team developed OHSC in which microglia from the hippocampus of living mice of different ages could be integrated into the system. The researchers used wild-type mice aged five weeks and six months as well as transgenic Alzheimer’s mice of the same ages, but whose brain cells overexpressed beta amyloid. The microglial cells that were added to the microglia-free slices, spread and differentiated completely normally, just as they would in vivo. The researchers found that the microglia of wild-type mice prevented plaques from forming effectively, in both the five-week and six-month-old mice. In transgenic Alzheimer’s mice, however, this only happened in the five-week-old cells.” Microglia isolated from brains with plaques were no longer able to prevent the formation of amyloid plaques. The ability of microglial cells to inhibit the formation of plaques therefore correlates with the appearance of plaques in vivo. However, it is not yet known why microglial cells are unable to do so once amyloid has formed. The researchers assume that the microglia from the transgenic Alzheimer’s disease mice, in response to a given stimulus, undergo the same phagocytosis, motility and morphology changes as old cells.

Microglia manipulation as potential therapy?

In the near future, Biber plans to carry out further investigations, including mRNA expression analyses, to determine the changes microglial cells undergo at certain points in time, and that indicate the onset of plaque formation. Biber believes that microglia manipulation will eventually play an important role in the prevention and/or treatment of Alzheimer’s disease. “If we are able to understand on the molecular level what reduces phagocytosis and discover that this precedes plaque formation, we will be able to develop a drug that prevents plaque formation.

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