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

Carlo, A.S.; Gustafsen, C.; Mastrobuoni, G.; Nielsen, M.S.; Burgert, T.; Hartl, D.; Rohe, M.; Nykjaer, A.; Herz, J.; Heeren, J.; Kempa, S.; Petersen, C.M.; Willnow, T.E.

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., Gustafsen, C., Mastrobuoni, G., Nielsen, M.S., Burgert, T., Hartl, D., Rohe, M., Nykjaer, A., Herz, J., Heeren, J., Kempa, S., 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
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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