Microglia-astrocyte crosstalk as a key organizing principle of Alzheimer's disease: from homeostatic cooperation to maladaptive signaling loops.

Alzheimer's disease (AD) has long been framed around amyloid-beta (Aβ) and tau pathology, yet mounting evidence indicates that dysfunctional microglia-astrocyte crosstalk is an important, and often underappreciated, contributor to disease progression that operates alongside-rather than in place of-neuronal, vascular, and proteinopathic mechanisms. Here we propose a three-stage framework in which glial communication transitions from silent vulnerability through organized defense to maladaptive collapse. During preclinical aging, gut dysbiosis, diminished tryptophan-derived aryl hydrocarbon receptor (AHR) ligands, and blood-brain barrier weakening prime glia toward inflammatory states with elevated complement tone. Upon Aβ accumulation, microglia and astrocytes initially mount a compensatory response-forming reactive glial nets, containing plaques, clearing tau, and executing complement-guided synaptic pruning. However, sustained pathological burden triggers self-reinforcing loops involving the C3-C3aR axis and IL-1α/TNF-α/C1q signaling, converting the glial network into a propagation engine for tau spreading and synapse loss-the strongest correlate of cognitive decline. We discuss the tryptophan-microbiota-AHR axis as one candidate upstream modulator, while emphasizing that direct human evidence remains limited, and highlight APOE4 in exacerbating microglia-dependent synaptic phagocytosis. To support testability, we operationally define maladaptive loops and communication collapse, and specify measurable variables, fluid/imaging biomarker proxies (e.g., the sTREM2/GFAP ratio), and falsifiable predictions. This framework, presented as an integrative hypothesis rather than an established principle, argues that future therapies must combine protein-targeted approaches with restoration of glial communication homeostasis.