The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain
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The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain. / Carlo, Anne-Sophie; Gustafsen, Camilla; Mastrobuoni, Guido; Nielsen, Morten S; Burgert, Tilman; Hartl, Daniela; Rohe, Michael; Nykjaer, Anders; Herz, Joachim; Heeren, Joerg; Kempa, Stefan; Petersen, Claus Munck; Willnow, Thomas E.
in: J NEUROSCI, Jahrgang 33, Nr. 1, 02.01.2013, S. 358-70.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain
AU - Carlo, Anne-Sophie
AU - Gustafsen, Camilla
AU - Mastrobuoni, Guido
AU - Nielsen, Morten S
AU - Burgert, Tilman
AU - Hartl, Daniela
AU - Rohe, Michael
AU - Nykjaer, Anders
AU - Herz, Joachim
AU - Heeren, Joerg
AU - Kempa, Stefan
AU - Petersen, Claus Munck
AU - Willnow, Thomas E
PY - 2013/1/2
Y1 - 2013/1/2
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Vesicular Transport
KW - Amyloid beta-Peptides
KW - Animals
KW - Apolipoproteins E
KW - Astrocytes
KW - Brain
KW - Low Density Lipoprotein Receptor-Related Protein-1
KW - Mice
KW - Neurons
KW - Plaque, Amyloid
U2 - 10.1523/JNEUROSCI.2425-12.2013
DO - 10.1523/JNEUROSCI.2425-12.2013
M3 - SCORING: Journal article
C2 - 23283348
VL - 33
SP - 358
EP - 370
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 1
ER -