Cerebrovascular Effects of Apolipoprotein E:  Implications for Alzheimer Disease

Figure 1. A schematic showing that astrocyte-secreted apolipoprotein E2 (apoE2) and apoE3, but not apoE4, signal to pericytes via low-density lipoprotein receptor-related protein 1 (LRP1), suppressing the cyclophilin A (CypA)–nuclear factor κB (NFκB)–matrix metalloproteinase 9 (MMP-9) proinflammatory pathway that causes blood-brain barrier (BBB) breakdown by MMP-9–mediated degradation of tight junction and basement membrane proteins. Dysfunction of the BBB is associated with accumulation of several neurotoxins in the brain, affecting neuronal function and contributing to the development of neurodegenerative changes. Modified from Bell et al.¹³

Figure 2. The role of blood-brain barrier (BBB) clearance in homeostasis of β-amyloid (Aβ) in brain. Binding of Aβ to apolipoprotein E (apoE) and clusterin (CLU, also referred to as apoJ) in brain interstitial fluid influences its aggregation and clearance from brain across the BBB via low-density lipoprotein receptor-related protein 1 (LRP1) and LRP2. In contrast to rapid clearance of free Aβ40/42 and their complexes with apoE2 or apoE3 at the BBB via LRP1, Aβ-apoE4 is redirected to a slow very low-density lipoprotein receptor (VLDLR)–mediated clearance mechanism and is subsequently eliminated from brain at a significantly slower rate. The LRP2 contributes to rapid efflux of Aβ-CLU complexes from brain. TJ indicates tight junction. Modified from Deane et al¹⁶ and Bell et al.¹⁸

Figure 3. Proposed role of apolipoprotein E (apoE) isoform-specific effects on the cerebrovascular system via regulation of the cyclophilin A (CypA)–nuclear factor κB (NFκB)–matrix metalloproteinase 9 (MMP-9) pathway and β-amyloid (Aβ) clearance. A, Astrocyte (A)–secreted apoE2 or apoE3 interacts with low-density lipoprotein receptor-related protein 1 (LRP1) on pericytes (P) and suppresses the proinflammatory CypA-NFκB–MMP-9 pathway, which maintains blood-brain barrier (BBB) integrity. Additionally, apoE2 and apoE3 interact with LRP1 in the endothelial cells (E) to mediate Aβ clearance from brain to blood. B, Astrocyte (A)–secreted apoE4 interacts weakly with LRP1 in pericytes (P) and endothelial cells (E), and its binding to LRP1 on vascular cells is barely detectable. In pericytes, this weak interaction results in increased intracellular CypA; this activates the proinflammatory NFκB–MMP-9 pathway, leading to BBB disruption and accumulation of neurotoxic blood-derived molecules in brain and causing neuronal injury. In endothelial cells, the weak interaction between apoE4 and LRP1 fails to efficiently remove Aβ from brain, contributing to Aβ accumulation and Aβ-mediated neuronal injury. BM indicates basement membrane; TJ, tight junction.