2,2',4'-trihydroxychalcone from Glycyrrhiza glabra as a new specific BACE1 inhibitor efficiently ameliorates memory impairment in mice.
Alzheimer's disease (AD) characterizes a progressive neurodegenerative disorder of the brain, while AD patients are afflicted with irreversible loss of neurons and further the intellectual abilities including memory and reasoning. One of the typical hallmarks of AD is the deposition of senile plaque that is contributed mainly by amyloid-beta (Abeta), whose production is initiated by beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1). Inhibition of BACE1 is thereby regarded as an attractive strategy for anti-AD drug discovery. Here, we reported that the natural product 2,2',4'-trihydroxychalcone (TDC) from Glycyrrhiza glabra functioned as a specific non-competitive inhibitor against BACE1 enzyme, and potently repressed beta-cleavage of APP and production of Abeta in human embryo kidney cells-APPswe cells. Moreover, the amelioration ability of this compound against the in vivo memory impairment was further evaluated by APP-PS1 double transgenic mice model. It is discovered that treatment of 9 mg/kg/day of TDC could obviously decrease Abeta production and Abeta plaque formation, while efficiently improve the memory impairment based on Morris water maze test. Our findings thus demonstrated that the natural product TDC as a new BACE1 inhibitor could ameliorate memory impairment in mice, and is expected to be potentially used as a lead compound for further anti-AD reagent development.
Zhu
Zhiyuan
Z
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Li
Chenjing
C
Wang
Xu
X
Yang
Zhengyi
Z
Chen
Jing
J
Hu
Lihong
L
Jiang
Hualiang
H
Shen
Xu
X
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D006035:Glycyrrhiza; D006801:Humans; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000187:drug effects / Q000502:physiology
C110093:2,4,2'-trihydroxychalcone; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047188:Chalcones; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse