FigureFigure 1
Multifaceted effects of APOE in the brain and potential strategies to decrease APOE4 and increase APOE2 levels. In the healthy brain, APOE is expressed and secreted predominantly by astrocytes, and to a lesser extent by microglia. Most brain APOE is lipidated by the ATP-binding cassettes A1 (ABCA1) and G1 (ABCG1) and lipidated APOE is internalized via APOE receptors such low-density lipoprotein receptor-related protein 1 (LRP1), which is expressed in astrocytes, neurons, vascular smooth muscle cells, endothelial cells, and pericytes. In the Alzheimer’s disease brain, astrocytes and microglia react to (A) dense-core Aβ plaques 63 , (B) cerebral amyloid angiopathy-laden arteries and capillaries, and (C) neurofibrillary tangles, activating transcriptional programmes that include APOE mRNA up-regulation in microglia 35 , 37 and down-regulation in astrocytes 35 , 36 and lead to altered lipid metabolism (not shown). APOE directly interacts with both soluble and fibrillar Aβ. Relative to