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Hypothetical stage-dependent involvement of astrocytes in the pathogenesis of ALS/FTD

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(1) Under physiological conditions, astrocytes engage in homeostatic signaling with neurons (thick green arrow) and other glial cell types to maintain the optimal milieu within the CNS. (2) The expression of ALS/FTD-mutant proteins or other environmental insults is sufficient to trigger an inflammatory response in astrocytes, diverting them from their housekeeping role (medium green arrow) towards a potentially harmful mutual interplay with neurons (red arrows). (3) As neurodegeneration settles in, astrocytes are likely to acquire a full-flown neuroinflammatory phenotype that exerts further neurotoxic signaling, in cooperation with other glial cells (red arrows), compensatory neuroprotective messengers (blue arrow), and reduced trophic support (thin green arrow). (From: Valori CF, Sulmona C, Brambilla L, Rossi D. Astrocytes: dissecting their diverse roles in amyotrophic lateral sclerosis and frontotemporal dementia. Cells 2023;12[11]:1450. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)