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

Abstract

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.