The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the Brain

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

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease.Amongother functions,APOEis 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 APOEdeficient 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.

Original languageEnglish (US)
Pages (from-to)358-370
Number of pages13
JournalJournal of Neuroscience
Volume33
Issue number1
DOIs
StatePublished - Jan 2 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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