title: Amyloid beta₁₋₄₂ (Aβ₄₂) up-regulates the expression of sortilin via the p75(NTR)/RhoA signaling pathway.
abstract: 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.
authors.affiliation: School of Pharmacy and Medical Sciences, Faculty of Health Sciences, University of South Australia, Adelaide, SA, Australia; Department of Human Physiology, Centre for Neuroscience, University of Flinders, Adelaide, SA, Australia.
authors.forename: Khalil
authors.initials: K
authors.lastname: Saadipour
authors.forename: Miao
authors.initials: M
authors.lastname: Yang
authors.forename: Yoon
authors.initials: Y
authors.lastname: Lim
authors.forename: Kristen
authors.initials: K
authors.lastname: Georgiou
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Damien
authors.initials: D
authors.lastname: Keating
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Ye-Ran
authors.initials: YR
authors.lastname: Wang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Gai
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Zhong
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis*; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D053764:Presenilin-1 / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor; D020742:rhoA GTP-Binding Protein; D000099183:Sortilin; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Aβ42; RhoA signaling pathway; p75NTR; sortilin