Cryptotanshinone, a compound from Salvia miltiorrhiza modulates amyloid precursor protein metabolism and attenuates beta-amyloid deposition through upregulating alpha-secretase in vivo and in vitro.
The amyloid precursor protein (APP) is cleaved enzymatically by non-amyloidogenic and amyloidogenic pathways. alpha-Secretase cleaves APP within beta-amyloid protein (Abeta) sequence, resulting in the release of a secreted fragment of APP (sAPPalpha) and precluding Abeta generation. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). However, the effects of CTS on the Abeta plaque pathology and the APP processing in AD are unclear. Here we reported that CTS strongly attenuated amyloid plaque deposition in the brain of APP/PS1 transgenic mice. In addition, CTS significantly improved spatial learning and memory in APP/PS1 mice assessed by the Morris water maze testing. To define the exact molecular mechanisms involved in the beneficial effects of CTS, we investigated the effects of the CTS on APP processing in rat cortical neuronal cells overexpressing Swedish mutant human APP695. CTS was found to decrease Abeta generation in concentration-dependent (0-10muM) manner. Interestingly, the N-terminal APP cleavage product, sAPPalpha was markedly increased by CTS. Further study showed that alpha-secretase activity was increased by CTS. Taken together, our results suggested CTS improved the cognitive ability in AD transgenic mice and promoted APP metabolism toward the non-amyloidogenic products pathway in rat cortical neuronal cells. CTS shows a promising novel way for the therapy of AD.
Mei
Zhengrong
Z
Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
Zhang
Fangyan
F
Tao
Liang
L
Zheng
Wenhua
W
Cao
Yingnan
Y
Wang
Zhaohe
Z
Tang
Shu
S
Le
Kang
K
Chen
Shaorui
S
Pi
Rongbiao
R
Liu
Peiqing
P
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001892:Camphanes; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053723:Panax notoginseng; D010616:Phenanthrenes / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001892:Camphanes; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D053764:Presenilin-1; C000604051:danshen dripping pill; C037886:cryptotanshinone; D053829:Amyloid Precursor Protein Secretases