title: Sortilin-related receptor 1 interacts with amyloid precursor protein and is activated by 6-shogaol, leading to inhibition of the amyloidogenic pathway.
abstract: Sortilin-related receptor 1 (SORL1) is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate amyloid beta (Aβ). Although 6-shogaol, a constituent of ginger, has been reported to have anti-inflammatory and anti-oxidant effects on neuronal cells, research regarding the activation of SORL1 has not yet been reported. Here, we aimed to investigate whether 6-shogaol contributes to the increases in SORL1 that are related to Alzheimer's disease (AD). To clarify the effect of 6-shogaol as a possible activator of SORL1, we used SORL1 siRNA as a blockade of SORL1 in hippocampal neuronal cells (HT22). We found that SORL1 siRNA treatment naturally inhibited SORL1 and led to increases in β-secretase APP cleaving enzyme (BACE), secreted APP-β (sAPPβ) and Aβ. In contrast, 6-shogaol-mediated activation of SORL1 significantly downregulated BACE, sAPPβ, and Aβ in both in vitro HT22 cells and in vivo APPSw/PS1-dE9 Tg mice. Therefore, SORL1 activation by 6-shogaol provides neuronal cell survival through the inhibition of Aβ production. These results indicate that 6-shogaol should be regarded as an SORL1 activator and a potential preventive agent for the treatment of AD.
authors.affiliation: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan 54596, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Na
authors.affiliation: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan 54596, Republic of Korea.
authors.forename: Kibbeum
authors.initials: K
authors.lastname: Song
authors.affiliation: Central Research and Development, Between Ltd, Iksan 54596, Republic of Korea.
authors.forename: Ju-Woon
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan 54596, Republic of Korea. Electronic address: raios@hanmail.net.
authors.forename: Sokho
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonbuk National University, 79 Gobongro, Iksan 54596, Republic of Korea; Central Research and Development, Between Ltd, Iksan 54596, Republic of Korea. Electronic address: jkwon@jbnu.ac.kr.
authors.forename: Jungkee
authors.initials: J
authors.lastname: Kwon
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000008:administration & dosage*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D002396:Catechols; D026901:Membrane Transport Proteins; D009153:Mutagens; D011973:Receptors, LDL; C491168:Sorl1 protein, mouse; C040115:shogaol
keywords: 6-Shogaol; APP; APP/PS1 mice; Alzheimer's disease; SORL1