Document Detail


The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain.
MedLine Citation:
PMID:  23283348     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β (Aβ) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aβ complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aβ catabolism and pro-neurotrophin signaling converging on this receptor.
Authors:
Anne-Sophie Carlo; Camilla Gustafsen; Guido Mastrobuoni; Morten S Nielsen; Tilman Burgert; Daniela Hartl; Michael Rohe; Anders Nykjaer; Joachim Herz; Joerg Heeren; Stefan Kempa; Claus Munck Petersen; Thomas E Willnow
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  33     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-03-12     Revised Date:  2014-02-25    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  358-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Vesicular Transport / metabolism*
Amyloid beta-Peptides / metabolism*
Animals
Apolipoproteins E / metabolism
Astrocytes / metabolism
Brain / metabolism*
Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
Mice
Neurons / metabolism*
Plaque, Amyloid / metabolism
Grant Support
ID/Acronym/Agency:
P01 HL020948/HL/NHLBI NIH HHS; R01 HL063762/HL/NHLBI NIH HHS; R37 HL063762/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Vesicular Transport; 0/Amyloid beta-Peptides; 0/Apolipoproteins E; 0/Low Density Lipoprotein Receptor-Related Protein-1; 0/sortilin
Comments/Corrections
Comment In:
Prion. 2013 Sep-Oct;7(5):378-82   [PMID:  24121631 ]

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