ApoE Promotes the Proteolytic Degradation of Aβ
| Autor: | Noam Zelcer, Timothy M. Willson, C. Y. Daniel Lee, Jill C. Richardson, Shweta Mandrekar, David M. Holtzman, Jon L. Collins, Jonathan D. Smith, Qingguang Jiang, Gary E. Landreth, David Riddell, Paige E. Cramer, Karen Mann, Peter Tontonoz, Brandy L. Wilkinson, Bruce T. Lamb, Thomas A. Comery |
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| Přispěvatelé: | Other departments |
| Rok vydání: | 2008 |
| Předmět: |
Apolipoprotein E
Aging Benzylamines Time Factors HUMDISEASE Receptors Cytoplasmic and Nuclear Plaque Amyloid Benzoates Mice 0302 clinical medicine Receptor Neprilysin Cells Cultured Liver X Receptors 0303 health sciences Microglia Behavior Animal General Neuroscience Brain Orphan Nuclear Receptors Cell biology DNA-Binding Proteins medicine.anatomical_structure Biochemistry lipids (amino acids peptides and proteins) Alzheimer's disease ATP Binding Cassette Transporter 1 Agonist medicine.drug_class Neuroscience(all) Enzyme-Linked Immunosorbent Assay Mice Transgenic Biology MOLNEURO Article 03 medical and health sciences Apolipoproteins E Alzheimer Disease Memory mental disorders medicine Animals Liver X receptor 030304 developmental biology Amyloid beta-Peptides Dose-Response Relationship Drug medicine.disease Peptide Fragments nervous system diseases Mice Inbred C57BL Disease Models Animal Animals Newborn CELLBIO ATP-Binding Cassette Transporters 030217 neurology & neurosurgery Homeostasis |
| Zdroj: | Neuron, 58(5), 681-693. Cell Press |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2008.04.010 |
| Popis: | Apolipoprotein E is associated with age-related risk for Alzheimer’s disease and plays critical roles in Aβ homeostasis. We report that ApoE plays a previously unappreciated role in facilitating the proteolytic clearance of soluble Aβ from the brain. The endolytic degradation of Aβ peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Aβ degradation extracellularly by insulin degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Aβ 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 Aβ degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Aβ load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a novel mechanism through which ApoE facilitates the clearance of Aβ from the brain and suggest that LXR agonists may represent a novel therapy for AD. |
| Databáze: | OpenAIRE |
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