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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

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Item Type:Article
Title:The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain
Creators Name:Carlo, A.S. and Gustafsen, C. and Mastrobuoni, G. and Nielsen, M.S. and Burgert, T. and Hartl, D. and Rohe, M. and Nykjaer, A. and Herz, J. and Heeren, J. and Kempa, S. and Petersen, C.M. and Willnow, T.E.
Abstract:Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-{beta} (A{beta}) 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/A{beata} complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of A{beta} in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/A{beta} 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 A{beta} catabolism and pro-neurotrophin signaling converging on this receptor.
Keywords:Amyloid beta-Peptides, Amyloid Plaque, Apolipoproteins E, Astrocytes, Brain, Low Density Lipoprotein Receptor-Related Protein-1, Neurons, Vesicular Transport Adaptor Proteins, Animals, Mice
Source:Journal of Neuroscience
ISSN:0270-6474
Publisher:Society for Neuroscience (U.S.A.)
Volume:33
Number:1
Page Range:358-370
Date:2 January 2013
Official Publication:https://doi.org/10.1523/JNEUROSCI.2425-12.2013
PubMed:View item in PubMed

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