Figure 3.

Complex interactions between intracellular cascades result in a unique pattern of astrocyte reactivity in ND. (1) Many signals can trigger astrocyte reactivity (see Section How do Astrocytes become Reactive? and Figure 1) such as cytokines, purines or abnormal epitopes like aggregated proteins. Astrocytes may also react to the absence of “resting signals” from neighboring cells, which occurs with neuronal death in ND. (2) These molecular signals are detected by specific receptor complexes at the astrocyte membrane, which activate several signaling cascades such as the JAK/STAT3 pathway, the NF-κB pathway, and the MAP kinase pathway (see also Figure 1). These pathways and their effectors interact either directly or indirectly, in the cytoplasm, in the nucleus, or on DNA promoter regions (see Section Additional Levels of Complexity). Recent studies support the idea that these cascades eventually converge on the JAK/STAT3 pathway, triggering a transcriptional program of reactivity in astrocytes. This program is modulated at several levels. (3) Disease-specific proteins (mHtt, mSOD1) endogenously expressed in astrocytes as well as internalized aggregated proteins (Aβ) can directly interfere with these signaling cascades or with transcriptional activity. (4) Several environmental factors may also affect the transcriptional program in reactive astrocytes, such as nuclear factors (other transcription factors, chromatin state) and environmental factors (age, sex). In the brain, dialog with other cell types or the specific brain regions involved is another potential level of modulation. These complex signaling cascades result in (5a) common features of astrocyte reactivity such as the upregulation of GFAP and cellular hypertrophy and (5b) disease-specific outcomes. This scheme illustrates how several signals can converge on a central signaling cascade that, in turn, is modulated in a disease- and environment-specific manner to produce a particular functional outcome.