TY - JOUR
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.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.
AB - 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.
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U2 - 10.1523/JNEUROSCI.2425-12.2013
DO - 10.1523/JNEUROSCI.2425-12.2013
M3 - Article
C2 - 23283348
AN - SCOPUS:84871769571
SN - 0270-6474
VL - 33
SP - 358
EP - 370
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -