Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid beta-protein in cultured cells.
Amyloid beta-protein (A beta) is a pivotal pathological factor in Alzheimer's disease (AD). Tenuigenin, extracted from the Chinese herb Polygala tenuifolia, seems to ameliorate the reduction in cholinergic function on rat models induced by A beta. To examine this therapeutic effect, we tested whether Tenuigenin could inhibit secretion of A beta in neuroblastoma cells stably transfected with two amyloid precursor protein (APP) constructs: the APP695 cDNA (SH-SY5Y APP695) and the C-terminal 99 amino acid residues of APP plus the signal peptide (SH-SY5Y SPA4CT). Tenuigenin inhibited the secretion of A beta and the C-terminal 99 amino acids of APP (C99) in SH-SY5Y APP695 cells, but did not change the A beta and C99 levels in SH-SY5Y SPA4CT cells. Fluorescence Resonance Energy Transfer (FRET) assays showed that Tenuigenin inhibited the proteolytic activities of BACE1 (beta-secretase) on its substrate in vitro. In addition, Tenuigenin did not demonstrate any cytotoxic effects, nor did it affect APP mRNA expression, holoAPP synthesis or sAPP alpha secretion. Our data suggest that Tenuigenin can inhibit the secretion of A beta in SH-SY5Y APP 695 cells via BACE1 inhibition. Taken together, these results suggest that Tenuigenin may be worthy of future study as an anti-AD drug.
Jia
Hongxiao
H
Department of Biochemistry, Institute of Mental Health, Peking University, No. 51 Hua Yuan Bai Road, 100083 Beijing, China.
Jiang
Yong
Y
Ruan
Yan
Y
Zhang
Yanbo
Y
Ma
Xin
X
Zhang
Jizhi
J
Beyreuther
Konrad
K
Tu
Penfei
P
Zhang
Dai
D
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D010450:Endopeptidases; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D007770:L-Lactate Dehydrogenase; D009447:Neuroblastoma; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004365:Drugs, Chinese Herbal; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; C493220:tenuigenin; D007770:L-Lactate Dehydrogenase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C022616:thiazolyl blue