The forgotten half of the brain to recover memory

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Astrocytes from mice with Alzheimer’s disease. Genetically modified astrocAstrocytes from mice with Alzheimer’s disease. Genetically modified astrocytes allow neurons to survive Alzheimer’s disease. Mice treated in this way do not lose their memory. Photo: Department of Basic Neuroscience UNIL
A research team at the University of Lausanne has succeeded in preserving the memory of Alzheimer’s mice by boosting the metabolic functions of glial cells rather than neurons, a striking shift in treatment strategies. The results can be found in the journal "Glia".

Alzheimer’s disease progressively affects the memory until the loss of autonomy of individuals. It causes the death of neurons in the brain regions where the memory and learning mechanisms are located. Since treatment strategies focused on neurons have so far failed, researchers at the University of Lausanne (UNIL) have decided to change the paradigm by turning to a type of cell little considered by neuroscientists and supposedly spared by Alzheimer’s disease: astrocytes. Astrocytes are part of the glial cell family and are known for their useful properties in the structural and functional support of neurons. Neuroscientists from the University of Lausanne have focused on one of their proteins, UCP4, present in their mitochondria, which are the energy centers of the cells. By overexpressing UCP4 in the astrocytes of animal models of the disease, in this case Alzheimer’s mice, the University of Lausanne team succeeded in preventing the multiple degradations induced in neurons. The study, to be discovered in the journal Glia, shows that Alzheimer mice treated early do not lose their memory at an advanced age.

Alzheimer’s disease affected 35.6 million people worldwide in 2015, according to the WHO. It is constantly on the rise, with a doubling of cases expected every 20 years. It affects essential cognitive functions such as memory, language, reasoning and spatial orientation, up to a total loss of autonomy. This damage is attributed to the alteration of the neurons that make up the brain areas important for memory and learning, particularly the hippocampus. The pathology is characterized by the presence of plaques constituted by an accumulation of ß-amyloid protein between the neurons and by the presence of neurofibrillary tangles in the neurons. They would progressively cause the dysfunction of the latter until their death, explaining the decrease in volume of the hippocampus and the loss of cognitive functions observed in patients.

To date, there is no cure and the effectiveness of current approaches is questioned. These are essentially indirect treatments that aim to increase cognitive functions such as memory and attention. The numerous studies and trials aimed at amyloid plaques or neurofibrillary tangles have produced disappointing results," says Jean-Yves Chatton, a neuroscience researcher and director of the Department of Fundamental Neuroscience at the University of Lausanne’s Faculty of Biology and Medicine. It is therefore urgent to find new strategies to fight against this dementia.

An intact memory
Rather than acting on neurons, plaques or tangles, Jean-Yves Chatton’s research team focused on astrocytes, glial cells often neglected by neuroscientists. Since direct approaches are not very effective, the idea was to find an indirect way to preserve neurons by relying on cells that are not affected by the disease themselves, and therefore theoretically healthy, and moreover known for their healing capacities towards neurons," says the professor from the University of Lausanne.

For this study, his research team developed an approach to increase a function of astrocytes known to preserve neuronal death. The results show that this new strategy is able to counteract the pathological alterations observed in mice with Alzheimer’s disease, such as early disruption of cerebral metabolism, hippocampal atrophy, changes in neuronal structure and aberrant neuronal excitability. Remarkably, the memory of Alzheimer mice is preserved.

Boosting mitochondria in astrocytes
Astrocytes provide structural and functional support to neurons, notably through the exchange of substances that act on the neuronal plasticity mechanisms that underlie memory processes or by providing energy. Astrocytes are also known to have a respiration and energy production machinery - the mitochondria - that favors antioxidant conditions, which makes them particularly resistant to oxidative stress. The early stages of the disease are precisely associated with a metabolic disorder and the presence of oxidative stress. All this places them in one way or another at the heart of the problem", explains Nadia Rosenberg, first author of the study and research assistant at the Department of Basic Neurosciences of the University of Lausanne.

Based on this reasoning, Jean-Yves Chatton’s laboratory sought to reinforce the antioxidant functions of astrocytes by expecting a protective effect on neurons. To do this, he focused on a protein, UCP4. The role of this protein is to lower the oxidation produced by mitochondria when they generate energy by consuming oxygen. A previous study showed that when UCP4 was overexpressed in the mitochondria of astrocytes, it improved the function of neurons by a mechanism that is still poorly understood. We produced viruses capable of infecting astrocytes and delivering UCP4 into their mitochondria," says the researcher. By doing this, they have succeeded in diverting Alzheimer’s mice from their pathological trajectories.

A gateway to new treatment strategies
The results of the study show that targeting astrocytes and their mitochondria is an effective strategy to prevent the neuronal decline observed during the early stages of the disease. The approach used in this study, delivering genes to mice using viruses, is the equivalent of gene therapy in humans. However, it is too early to speak of a potential treatment, especially since gene therapies are still in their infancy. On the other hand, the study opens up solid avenues of exploration. We will now identify precisely the molecules and mechanisms that link UCP4 to the development of Alzheimer’s disease. This future research could lead to the identification of a drug treatment.