Fig. 2
From: Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Microglial activation and neurodegeneration. Aging induces microglial activation by activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. Misfolded proteins and protein aggregates induce microglial activation by impairing microglial autophagy. Stage-1 DAM represents a transitory and functional subtype with a higher capacity of phagocytosis initiated by a TREM2-independent mechanism, whereas stage-2 DAM represents a dysfunctional state initiated by a TREM2-dependent mechanism. The microglial spleen tyrosine kinase (SYK) signaling provides metabolic support to facilitate microglial transition into stage-2 DAM. Maladaptive microglial-T-cell signaling drives neurodegeneration by releasing neurotoxic factors. Microglial activation creates a feed-forward vicious cycle that aggravates neurodegeneration as activated microglia contribute to the propagation of protein aggregates into unaffected brain regions. This figure was created with BioRender (https://biorender.com/)
