ApoE promotes the proteolytic degradation of Abeta

• Published in: Neuron (Cambridge, Mass.) Vol. 58; no. 5; p. 681
• Main Authors: Jiang, Qingguang, Lee, C Y Daniel, Mandrekar, Shweta, Wilkinson, Brandy, Cramer, Paige, Zelcer, Noam, Mann, Karen, Lamb, Bruce, Willson, Timothy M, Collins, Jon L, Richardson, Jill C, Smith, Jonathan D, Comery, Thomas A, Riddell, David, Holtzman, David M, Tontonoz, Peter, Landreth, Gary E
• Format: Journal Article
• Language: English
• Published: United States 12.06.2008
• Subjects: Aging; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Animals; Animals, Newborn; Apolipoproteins E - pharmacology; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; Behavior, Animal - drug effects; Benzoates - pharmacology; Benzylamines - pharmacology; Brain - pathology; Cells, Cultured; Disease Models, Animal; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay - methods; Liver X Receptors; Memory - drug effects; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - drug effects; Microglia - metabolism; Orphan Nuclear Receptors; Peptide Fragments - metabolism; Plaque, Amyloid - drug effects; Receptors, Cytoplasmic and Nuclear - metabolism; Time Factors
• ISSN: 1097-4199
• DOI: 10.1016/j.neuron.2008.04.010

Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD.