From Astrophysics to Astrocytes

Astrocytes are often thought of as cognitive custodians, halting the advance of Alzheimer’s by seeking out and destroying amyloid plaques. The mechanism has even been explored as a potential therapeutic target for Alzheimer’s disease, since a deficiency in astrocyte activity is believed to spur on disease advancement. But a new study that used spatial analysis and computer modeling to study astrocyte distribution in a mouse model of Alzheimer’s found that astrocytes are repelled by one another – and by amyloid plaques (1).

“The theory exists that both astrocytes and microglia move to the plaques and eat them up, and that impairment of this capacity contributes to Alzheimer´s disease,” says Elena Galea, a researcher from the Institute of Neuroscience at the Universitat Autònoma de Barcelona, and lead author of the study. “Our research suggests that this is not entirely true, and that our therapeutic efforts would be better focused on promoting plaque removal by microglia.”

The first challenge faced by the researchers was extracting information from the 3D images of live mouse brains for quantitative, mathematical study. “The images produced are non-standard, have a high degree of variability, and lack optimal cellular resolution,” says Galea. “We worked hard to develop a very intricate algorithm that allowed us to extract the elements of interest while removing false positives and artifacts.”

Having extracted the relevant information, the researchers used mathematical models to compare the observed astrocyte distribution to a reference system where everything is random. “We can tell that astrocytes sense one another’s presence because the probability of finding one astrocyte in the volume of cortical space surrounding another astrocyte is very small compared to a reference system of non-interacting cells,” says Galea. “We can also tell that plaques repel astrocytes because the volume of space that ‘belongs’ to an astrocyte near a plaque is likely to be larger than that of a reference astrocyte.”

The research also revealed that astrocytes try to separate from plaques and from other astrocytes, to the point that a “belt” exists around astrocytes that no other astrocyte enters. Galea suggests that these negative interactions may cause spatial tensions in brains with a lot of plaques – confined by the skull, the astrocytes have nowhere to go.

Galea and her colleagues hope to identify the substance or substances involved in keeping the astrocytes away from each other, and find out whether or not the spatial tension of astrocytes in Alzheimer´s disease affects the neuronal circuits supported by astrocytes. “Mathematics has done its job here: to help make predictions to be tested experimentally,” says Galea.