Figure 4.

Tryptophan participates in microglia and astrocyte crosstalk in AD with the involvement of MGBA. The tryptophan (Trp) metabolism regulates the interaction between microglia and astrocyte. Molecules, such as C3, TNF-α, control the interaction. The C3 originates from microglia-primed astrocytes and the TNF-α is released from astrocytes-primed microglia. The interaction of microglia and astrocyte affects their functions (e.g., phagocytosis and generation of ROS) that are essential pathological processes in AD. The metabolism of gut flora produces small molecules, such as Trp. The metabolites of Trp and Trp affect the interaction between microglia and astrocyte via ROS pathway. Trp regulates three major metabolic pathways (e.g., 5-HT, KYN, and AHR ligand pathways). Alteration in gut microbiota composition, Trp synthesis and its related metabolites lead to change in the pattern of microbiome within the gut. In the brain, Trp acts on the AHR to stimulate the production of QUIN and KYNA. The activation of microglia and astrocyte through AHR increases and decreases ROS through the release of QUIN and KYNA, resulting in neurotoxic and neuroprotective effects, respectively. The top three CMap gene connections of AHR are PI4KIIB, APOBEC3, and CHMP2A. Trp controls the microglia-astrocyte crosstalk in AD with the involvement of MGBA mechanisms. This figure was created with BioRender.com.