The human brain keeps billions of neurons functional across decades. Glia, the helper cells of the brain, are essential to maintaining this neural resilience: They react to neuronal states and carefully balance either quick repair or disposal of injured neurons to prevent damage spread. Malfunction of these interactions is implicated in many neurodegenerative diseases. Here, we propose a model for neuron-glia crosstalk which maintains tissue resilience by a balance between housekeeping and damage- inducing glial reactions to neuronal damage and death. Depending on the interplay of the functionality of this crosstalk, the model assumes four distinct tissue states: healthy, challenged, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. These states and their underlying mechanisms are in agreement with experimental observations for the most common neurodegenerative conditions. We suggest that the onset of neurodegeneration results from a compromise between two conflicting goals: Maintenance of short-term resilience to stressors, and resilience to degeneration. Based on these findings, we discuss disease-state specific diagnostic and therapeutic strategies.

A model of neuron-glia crosstalk explains stages of neural tissue resilience