Amyloid beta(1-42) (A beta(42)) up-regulates the expression of sortilin via the p75(NTR)/RhoA signaling pathway

作者：Saadipour Khalil; Yang Miao; Lim Yoon; Georgiou Kristen; Sun Ying; Keating Damien; Liu Jia; Wang Ye Ran; Gai Wei ping; Zhong Jin hua; Wang Yan Jiang; Zhou Xin Fu^*

来源：Journal of Neurochemistry, 2013, 127(2): 152-162.

DOI：10.1111/jnc.12383

• Alzheimer%26apos
• s disease
• A(42)
• p75(NTR)
• RhoA signaling pathway
• sortilin

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%26apos;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. A(42) 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- protein (A), suggesting that A(42) 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 A(42)-induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that A(42) oligomer increases sortilin gene and protein expression through p75(NTR) and RhoA signaling pathways, suggesting a potential physiological interaction of A(42) and sortilin in Alzheimer%26apos;s disease.

• 出版日期2013-10