Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing.

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.

• Authors: Sung Hee Hwang, Eun-Joo Shin, Tae-Joon Shin, Byung-Hwan Lee, Sun-Hye Choi, Jiyeon Kang, Hyeon-Joong Kim, Seung-Hwan Kwon, Choon-Gon Jang, Jun-Ho Lee, Hyoung-Chun Kim, Seung-Yeol Nah
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 31 Issue 1 Pg. 207-23 ( 2012) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 22543851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
• Aif1 protein, mouse
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Calcium-Binding Proteins
• Enzyme Inhibitors
• Glycoproteins
• Indans
• Isoxazoles
• Ligands
• Microfilament Proteins
• Nootropic Agents
• PSEN1 protein, human
• Peptide Fragments
• Piperidines
• Plant Proteins
• Presenilin-1
• Propionates
• Receptors, Lysophosphatidic Acid
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Egtazic Acid
• Donepezil
• Metalloproteases
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Calcium

Topics

• Alzheimer Disease (drug therapy, pathology)
• Amyloid beta-Peptides (metabolism, pharmacology)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Analysis of Variance
• Animals
• Brain (drug effects, metabolism)
• Calcium (metabolism)
• Calcium-Binding Proteins (metabolism)
• Cell Survival (drug effects)
• Disease Models, Animal
• Donepezil
• Dose-Response Relationship, Drug
• Egtazic Acid (analogs & derivatives, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Glycoproteins (pharmacology, therapeutic use)
• Humans
• Indans (pharmacology)
• Isoxazoles (pharmacology)
• Ligands
• Maze Learning (drug effects)
• Memory Disorders (chemically induced, drug therapy)
• Metalloproteases (metabolism)
• Mice
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Mutation (genetics)
• Neuroblastoma (pathology)
• Nootropic Agents (pharmacology)
• Panax (chemistry)
• Peptide Fragments (metabolism, pharmacology)
• Phytotherapy (methods)
• Piperidines (pharmacology)
• Plant Proteins (pharmacology, therapeutic use)
• Presenilin-1 (genetics)
• Propionates (pharmacology)
• Protein Binding (drug effects, physiology)
• Receptors, Lysophosphatidic Acid (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transfection