Amyloid beta _1-42 (Aβ ₄₂) up-regulates the expression of sortilin via the p75 ^NTR/RhoA signaling pathway

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice. Aβ₄₂ enhanced the protein and mRNA expression levels of sortilin in a dose- and time-dependent manner in SH-SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75^NTR (P75ECD-FC), or the antibody against the extracellular domain of p75^NTR, blocked the up-regulation of sortilin induced by Amyloid-β protein (Aβ), suggesting that Aβ₄₂ increased the expression level of sortilin and mRNA in SH-SY5Y via the p75^NTR receptor. Inhibition of ROCK, but not Jun N-terminal kinase, suppressed constitutive and Aβ₄₂- induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aβ₄₂ oligomer increases sortilin gene and protein expression through p75^NTR and RhoA signaling pathways, suggesting a potential physiological interaction of Aβ₄₂ and sortilin in Alzheimer's disease. Sortilin is the co-receptor of p75^NTR which signals the cell death induced by Aβ and proneurotrophins. We found that sortilin is increased in the AD brain and up-regulated by Aβ and pro-brain-derived neurotrophic factor (proBDNF). Aβ-induced upregulation of sortilin is mediated by p75^NTR and the down-streaming RhoA-ROCK signaling pathway. The Aβ/Sortilinp/75^NTR signaling may play a role in the pathogenesis of AD. Sortilin is the co-receptor of p75^NTR which signals the cell death induced by Aβ and proneurotrophins. We found that sortilin is increased in the AD brain and up-regulated by Aβ and pro-brain-derived neurotrophic factor (proBDNF). Aβ-induced upregulation of sortilin is mediated by p75^NTR and the down-streaming RhoA-ROCK signaling pathway. The Aβ/Sortilinp/75^NTR signaling may play a role in the pathogenesis of AD. Read the Editorial Highlight for this article on doi: 10.1111/jnc.12389.