In that mystery that is still in many respects the human brain, many are trying to put together the pieces of the puzzle to have a complete picture of diseases still without a cure, such as Alzheimer’s. Now a study coordinated by Michela Matteolifull professor of Pharmacology at Humanitas University and director of the Humanitas Neuroscience Program, investigated the role of the immune cells that reside in the brain, the microglial cells, in the development and maturation of the areas of the hippocampus responsible for memory, modifying the metabolism of neurons in these areas.
Dementia before the age of 65, 15 risk factors identified by Mara Magistroni 12 January 2024
More specifically, the research shows how some proteins implicated in neurodegenerative disorders have an important role already during the first years of life: “In a certain sense – explains Matteoli to Salute – it is as if the first seeds of these dysfunctions were present in the neurons already from the age of development, that phase that goes from just before giving birth to two years after birth”. Nothing that can help us predict an increased risk of getting ill in the future in childhood, the scholar underlines, but certainly another piece that fills a gap. And which shows, once again, how development and aging in the brain are two sides of the same coin. The study was carried out in collaboration with the group of Simona Lodatohead of the Humanitas Neurodevelopment Laboratory and professor of Histology and Embryology at Humanitas University, Katia Cortese of the University of Genoa and Rafael Arguello of the CNRS of Marseille.
How to recognize the first symptoms of Alzheimer’s? by Sara Carmignani 13 October 2023
Like a bush of synapses to be pruned
To understand the meaning of the work carried out by Matteoli’s group it is necessary to resort to a vegetal metaphor. “Let’s imagine a bush in spring that grows lush with its shoots. An explosion of disorderly vitality, which could worry any gardener, ready to prune here and there, cutting the weakest branches to bring some order to the tangle of vegetation. Well, in the age of development this is a bit what happens to the brain, human but not only. This is a particularly important moment for the formation of synapses, i.e. the contact points that allow the passage of information from one neuron to another. But, like in a bush, in this phase excess synapses form which must be eliminated.”
The role of immune cells in the brain
Microglial cells play the role of gardener armed with pruning shears. “It is a population of immune cells localized in the brain, which is activated in the presence of a lesion or damage,” explains Matteoli. These cells are therefore like controllers who, in case of emergency, move towards the region of damage and help repair it. In fact, they have a phagocytic capacity: their purpose is to “eat” cellular debris and eliminate it. In a non-pathological physiological situation, therefore, their role is to eliminate the excess of synapses that form during development.
Alzheimer’s, how diet influences the risk of dementia by Barbara Orrico 28 December 2023
The role of Trem 2 protein in brain development
Mediating this pruning process is the TREM 2 protein, expressed in microglia. This, adds the scholar, is an important factor because it has implications for all neurodegenerative diseases. In fact, in the absence of TREM 2, microglia are unable to eliminate debris present in the brain well, especially the amyloid protein, which accumulates and causes Alzheimer’s disease. “However – adds Matteoli – we wanted to study a different time window, that of development, where microglial cells play a thinning role by eliminating synapses that function less or are not used. In the absence of this protein there is therefore an excess of synapses, just like a bush that does not grow in the correct way.”
Alzheimer’s, 12 risk factors that can be acted upon by Sara Carmignani 07 December 2023
In the work just published, researchers led by Matteoli therefore went on to evaluate, in a mouse model, what happens in the brain immediately after birth when TREM 2 does not work correctly. “Since this protein is only expressed in microglia, we expected to find a malfunction in these cells. Instead we found that the absence of TREM 2 in microglia significantly alters the metabolism of neurons,” adds the scholar. Not only that: this destruction of neuronal metabolism particularly affects a region of the hippocampus, the structure that regulates learning and memory in mammals. This is the CA1 region, which is not surprisingly the first area involved during Alzheimer’s disease from the very early stages.
The discoveries
This work therefore demonstrates two things, concludes Matteoli. The first is that the neuron’s metabolism is not self-regulated, as we have always imagined, but depends on the microglia through the TREM 2 protein. “The other aspect that I find very interesting – adds the scholar – concerns the possibility that a mutation of TREM 2 associated with Alzheimer’s may already be active in the developmental phase.” This would result in already having metabolically poorly functional neurons which, with further damage resulting from aging or inflammation, would be more susceptible to neurodegeneration. The mechanism that links defective versions of TREM2 to the onset of Alzheimer’s is still being studied: discovering it could pave the way for the development of new therapeutic approaches for a disease that is still without effective treatments.