Fig 2: Expression of APOE4 in astrocytes and its roles in AD pathogenesis.

a, Healthy astrocytes produce and secrete most of the apolipoprotein E (APOE) found in the brain^39–41. This APOE participates in many astrocyte functions, including synaptic pruning, lipid homeostasis, clearance of amyloid β (Aβ) aggregates and cell debris and blood-brain barrier (BBB) support and maintenance^50–58. b, During stress and aging, astrocytic APOE4 contributes to astrocytic reactivity^43,50,51,59, elevated proinflammatory cytokine release^50,51,59, augmented mitochondrial dysfunction^63–66, and increased lipid synthesis^{31,53–55,60} and intracellular lipid accumulation^{31,51,53–55,60}. c, Astrocytic APOE4 also affects other CNS cells and can promote AD pathologies. For example, it drives an increase in microglial reactivity and adoption of a disease-associated microglia (DAM) phenotype⁴³. In addition, it contributes to AD pathogenesis by increasing astrocytic reactivity^43,50,51,59, the transition to a disease-associated astrocyte (DAA) phenotype⁷⁸, cytokine release^50,51,59, synaptic pruning^43,52 and lipid accumulation^{31,51,53–55,60}. In turn, these changes may lead to BBB leakiness^57,58,70, Aβ accumulation^51,54,71,74, tau accumulation^43,77 and (in conjunction with neuronal APOE4) synaptic and neuronal degeneration⁴³. The potential relationships among the effects of astrocytic APOE4 on other cells and AD pathologies are depicted using arrows. Note that non-astrocytic sources of APOE4 have been omitted from this figure for clarity. p-tau, hyperphosphorylated tau.