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

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. 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 -