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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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