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PMID: 18549781 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ApoE promotes the proteolytic degradation of Abeta.

Neuron ·Vol. 58 ·No. 5 ·2008-06-12 ·Pages 681-93

Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE

Abstract

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.

MeSH Terms
ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters/genetics Aging Alzheimer Disease/drug therapy,metabolism,pathology Amyloid beta-Peptides/metabolism Animals Animals, Newborn Apolipoproteins E/pharmacology Behavior, Animal/drug effects Benzoates/pharmacology Benzylamines/pharmacology Brain/pathology Cells, Cultured DNA-Binding Proteins/metabolism Disease Models, Animal Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay/methods Liver X Receptors Memory/drug effects Mice Mice, Inbred C57BL Mice, Transgenic Microglia/drug effects,metabolism Orphan Nuclear Receptors Peptide Fragments/metabolism Plaque, Amyloid/drug effects Receptors, Cytoplasmic and Nuclear/metabolism Time Factors
Chemicals
ATP Binding Cassette Transporter 1 ATP-Binding Cassette Transporters Amyloid beta-Peptides Apolipoproteins E Benzoates Benzylamines DNA-Binding Proteins GW 3965 Liver X Receptors Orphan Nuclear Receptors Peptide Fragments Receptors, Cytoplasmic and Nuclear amyloid beta-protein (1-42)
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Jiang Qingguang
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
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
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2008.04.010
Published
2008-06-12
Pages
681-93
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2493297
Subset
IM
Grants
NHLBI NIH HHS · HL66088 · United States
NIA NIH HHS · R01 AG030482-01 · United States
NHLBI NIH HHS · R01 HL066082 · United States
NIA NIH HHS · R01 AG013956 · United States
NIA NIH HHS · R01 AG020202 · United States
NIA NIH HHS · AG13956 · United States
NIA NIH HHS · R37 AG013956 · United States
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL066088 · United States
NHLBI NIH HHS · HL30568 · United States
NIA NIH HHS · F32AG24031 · United States
NIA NIH HHS · F32 AG024031 · United States
NIA NIH HHS · R01 AG030482 · United States
NHLBI NIH HHS · P01 HL030568 · United States
NIA NIH HHS · AG020202 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2008.04.010 PMC Full Text View journal details
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