title: The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain.
abstract: 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.affiliation: Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Carlo
authors.forename: Camilla
authors.initials: C
authors.lastname: Gustafsen
authors.forename: Guido
authors.initials: G
authors.lastname: Mastrobuoni
authors.forename: Morten S
authors.initials: MS
authors.lastname: Nielsen
authors.forename: Tilman
authors.initials: T
authors.lastname: Burgert
authors.forename: Daniela
authors.initials: D
authors.lastname: Hartl
authors.forename: Michael
authors.initials: M
authors.lastname: Rohe
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.forename: Stefan
authors.initials: S
authors.lastname: Kempa
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000099183:Sortilin