A schematic representation of a synapse, the left half illustrating the roles of microglia, astrocytes and the lipoprotein ligand ApoE in regulating Aβ release and degradation under physiological conditions. The right half illustrates how these processes can change in the context of AD. High concentrations of pathological (here shown as oligomeric) Aβ drive synaptic weakening, initially via AMPA receptor internalization (1). Several factors regulate local levels of the various forms of Aβ. Astrocytes serve numerous functions, including reuptake of released neurotransmitter as shown on the left of the figure. However, they also take up Aβ via scavenging receptors (2), a process that can be blocked by competitive binding of ApoE as shown on the right. Note that the AD risk associated variant ApoE4 has a particularly high affinity for Aβ scavenging receptors. In AD, microglia that have differentiated towards a phagocytic phenotype can also clear Aβ by phagocytosis (3), while a subpopulation of microglia also differentiates to a secretory phenotype with a far lower phagocytic capacity, this subtype becoming more prominent as the disease advances. These secrete a variety of pro-inflammatory mediators, including cytokines such as IL-1β and inflammasome-related multiprotein complexes known as ASC specks (4), which drive changes deleterious to neurons including the activation of caspases. Image created using Biorender.