The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain

Abstract

Apolipoprotein (APO) E is the major risk factor for sporadic Alzheimer disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-β peptides (Aβ) 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. In spite of 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. Taken 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.

SORLA regulates calpain‐dependent degradation of synapsin

“…In detail, it was reported that BDNF could only induce Sorl1 expression in iPSC that carried at least one protective receptor haplotype [35]. The authors also reported that, in line with previous work [36], BDNF only reduced Aβ production in cells capable of inducing SORLA, highlighting the importance of the interplay between SORLA and BDNF in the disease situation. The relevance of the here described SORLA-dependent control of synapsins should be explored in the context of BDNFdependent synaptic modulation in AD in future studies.…”

Role of Sortilin in Models of Autoimmune Neuroinflammation

“…Sortilin is expressed in various cell types, especially in the nervous system, including in cortical and hippocampal neurons, glia, and sympathetic neurons (7), as well as in nonneuronal tissue, such as that in muscle, liver, lung, testis, and thyroid gland. In line with this broad tissue distribution, sortilin has been implicated in various disorders, including Alzheimer's disease (8), frontotemporal lobar dementia (9), and seizures (10), as examples of CNS diseases, as well as in dyslipidemia and in the risk for myocardial infarction (11,12).…”

Apolipoprotein E Isoforms and AMD

“…In this context, ApoE, a component of lipoproteins (primarily chylomicrons, VLDL, and a subset of HDL particles), facilitates entry into cells by acting as a ligand for the low-density lipoprotein receptor (LDL-R), LDL-R like protein (LRP), heparan sulfate proteoglycans, and additional non-canonical receptors (Mahley and Rall 2000;Carlo et al 2013). E4 is highly enriched in VLDL particles due to its altered lipid-binding region that shows a preference for binding triglyceride-enriched particles.…”