Gintonin, a Ginseng-Derived Lysophosphatidic Acid Receptor Ligand, Attenuates Alzheimer's Disease-Related Neuropathies: Involvement of Non-Amyloidogenic Processing

Article type: Research Article

Authors: Hwang, Sung Hee^{a; 1} | Shin, Eun-Joo^{b; 1} | Shin, Tae-Joon^a | Lee, Byung-Hwan^a | Choi, Sun-Hye^a | Kang, Jiyeon^a | Kim, Hyeon-Joong^a | Kwon, Seung-Hwan^c | Jang, Choon-Gon^c | Lee, Jun-Ho^a | Kim, Hyoung-Chun^b | Nah, Seung-Yeol^{a; *}

Affiliations: [a] Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Korea | [b] Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Korea | [c] Department of Pharmacology, College of Pharmacy, Sungkyunkwan University, Suwon, Korea

Correspondence: [*] Correspondence to: Hyoung-Chun Kim, PhD, Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea. Tel.: +82 33 250 6917; Fax: +82 33 255 7865; E-mail: kimhc@kangwon.ac.kr and Seung-Yeol Nah, PhD, Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea. Tel.: +82 2 450 4154; Fax: +82 2 450 2809; E-mail: synah@konkuk.ac.kr.

Note: [1] These authors contributed equally to this study.

Abstract: Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Keywords: Alzheimer's disease, amyloid-β protein precursor, memory, transgenic mice

DOI: 10.3233/JAD-2012-120439

Journal: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 207-223, 2012