Protection against beta-amyloid

Immune cells of the brain protect it from Alzheimer's disease

Now we know that diseases of the central nervous system are closely related to the poor functioning of microglia – cells of the immune system located in the brain. Due to the high autonomy of the brain, it is not easy to study it, but now scientists have managed to grow a working experimental model from stem cells.

Historically, brain microglia cells have been classified as a subtype of "service" cells of the central nervous system. But in fact, they are immune cells – macrophages of bone marrow origin, i.e. they do not belong to the nervous system itself, strictly speaking. These cells appear at very early stages of embryonic development and migrate to the developing nervous system. Microglia functions autonomously: like the brain itself, it is separated from the rest of the body by a blood-brain barrier that does not pass pathogens and toxins.

Microglia plays an important role in the development and functioning of the brain. For example, in the process of neurogenesis, it performs "synaptic pruning" – reduces the number of redundant synapses (places of interaction of neurons) to increase the efficiency of neural networks. In the adult brain, microglial cells behave like typical macrophages: they protect the brain from bacteria and viruses, suppress inflammation, and work as "garbage collectors", such as the remains of dead neurons.

Microglial dysfunction is associated with the development of autism, schizophrenia, neurodegenerative diseases. Thus, its low activity presumably contributes to the formation of amyloid plaques in the brain – accumulations of the pathological protein beta-amyloid, characteristic of patients with Alzheimer's disease. On the other hand, in the case of excessive microglia in the brain, the destruction of nervous tissue is accelerated, which is also characteristic of neurodegenerative processes.

The question arises: after all, what type of microglial disorders is most closely associated with the development of Alzheimer's disease? To get an answer, we need model experiments on organoids of the human cerebral cortex – three-dimensional cellular structures of the developing brain grown "in vitro" from stem cells. But the standard technology for producing brain organoids does not provide for the use of microglia progenitor cells.

Now researchers from the USA have developed a method for creating functional microglia in brain organoids by overactivating in some of its cells just one gene encoding myeloid-specific transcription factor PU.1.

Unlike conventional brain organoids, there was no accumulation of beta-amyloid in organoids with such microglia-like cells. And the experimental addition of this pathological protein to them led to phagocytic activation of microglia, including a change in the activity of the corresponding genes. In other words, microglial cells began to absorb and utilize beta-amyloid.

These data support the hypothesis of the protective role of microglia in relation to Alzheimer's disease. In any case, scientists have managed to create a working model that will clarify the role of microglial cells in the development of not only Alzheimer's disease, but also other pathologies of the human brain.

Article by Cakir et al. Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids published in the journal Nature Communications.

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