Tenuigenin treatment decreases secretion of the Alzheimer’s disease amyloid β-protein in cultured cells

Amyloid β-protein (Aβ) 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 Aβ. To examine this therapeutic effect, we tested whether Tenuigenin could inhibit secretion of Aβ 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 Aβ and the C-terminal 99 amino acids of APP (C99) in SH-SY5Y APP695 cells, but did not change the Aβ and C99 levels in SH-SY5Y SPA4CT cells. Fluorescence Resonance Energy Transfer (FRET) assays showed that Tenuigenin inhibited the proteolytic activities of BACE1 (β-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 sAPPα secretion. Our data suggest that Tenuigenin can inhibit the secretion of Aβ 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.