Figure 1. ApoE Isoform Specific Effects in AD.

Amyloid-β (Aβ) is produced primarily by neurons in the brain (①) where it interacts with lipidated ApoE secreted by microglia and astrocytes (②) in an isoform specific manner. ApoE4 promotes the oligomerization and aggregation of Aβ (③) and the subsequent deposition of plaques (④) in vivo. Cell surface low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1) and heparan sulfate proteoglycan (HSPG) receptors mediate the endocytosis of Aβ by astrocytes and microglia. In addition to promoting the production and aggregation of Aβ, ApoE4 impairs Aβ clearance by reducing cellular uptake and transport across the blood brain barrier in vivo (⑤). ApoE2 overexpression enhances the proteolytic degradation of Aβ by insulin-degrading enzyme (IDE) and neprilysin produced by microglia and astrocytes (⑥). The enhanced proteolysis of neuronal ApoE4 by a chymotrypsin-like serine protease produces neurotoxic fragments (⑦). ApoE4-astrocytes exhibit reduced synaptic pruning capacity triggering the synaptic accumulation of the complement-component 1q (C1q) protein, possibly inducing complement pathway mediated neurodegeneration in vivo (⑧). ApoE4 expression also elicits a prolonged increase in pro-inflammatory cytokine secretion by astrocytes and microglia leading to chronic neuroinflammation and neurodegeneration (⑨). ApoE isoform specific roles in these processes are indicated. Figure was generated with the assistance of Biorender.