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7-Deoxy-trans-dihydronarciclasine Reduces β-Amyloid and Ameliorates Memory Impairment in a Transgenic Model of Alzheimer’s Disease

  • Yoon Sun Chun
  • Lijun Zhang
  • Huan Li
  • Yurim Park
  • Sungkwon Chung
  • Hyun Ok Yang
Article
  • 210 Downloads

Abstract

The critical pathological feature of Alzheimer’s disease (AD) is the accumulation of β-amyloid (Aβ), the main constituent of amyloid plaques. β-amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretase generating Aβ at endosomes or non-amyloidogenic processing by α-secretase precluding the production of Aβ at the plasma membrane. Recently, several natural products have been widely researched on the prevention of Aβ accumulation for AD treatment. We previously reported that Lycoris chejuensis K. Tae et S. Ko (CJ), which originated from Jeju Island in Korea, improved the disrupted memory functions and reduced Aβ production in vivo. Here, we further explored the effect of its active component, 7-deoxy-trans-dihydronarciclasine (coded as E144), on Aβ generation and the underlying mechanism. Our results showed that E144 reduced the level of APP, especially its mature form, in HeLa cells overexpressing human APP with the Swedish mutation. Concomitantly, E144 decreased the levels of Aβ, sAPPβ, sAPPα, and C-terminal fragment. In addition, administration of E144 normalized the behavioral deficits in Tg2576 mice, an APP transgenic mouse model of AD. E144 also decreased the Aβ and APP levels in the cerebral cortex of Tg2576 mice. Thus, we propose that E144 could be a potential drug candidate for an anti-amyloid disease-modifying AD therapy.

Keywords

Alzheimer’s disease β-amyloid precursor protein Cognition-improving effect 7-deoxy-trans-dihydronarciclasine β-amyloid 

Abbreviations

AD

Alzheimer’s disease

β-amyloid

APP

β-amyloid precursor protein

sAPPβ

APP ectodomain fragment β

CTFβ

APP C-terminal fragment β

sAPPɑ

APP ectodomain fragment α

CTFɑ

APP C-terminal fragment α

AICD

β-amyloid precursor protein intracellular domain

ADAM

A Disintegrin and Metalloproteinase

APPsw

APP carrying the Swedish mutation

imAPP

immature β-amyloid precursor protein

maAPP

mature β-amyloid precursor protein

CHX

cycloheximide

TG

transgenic

MWM

Morris water maze

NORT

novel object recognition test

BBB

blood-brain barrier

MAPK

mitogen-activated protein kinase

PI3-K

phosphoinositide-3-kinase

ERK

extracellular signal-regulated kinase

GSK

glycogen synthase kinase

Notes

Funding Information

This work was funded and supported by the Bio-Synergy Research Project (NRF-2012M3A9C4048793) and the Bio & Medical Technology Development Program (NRF-2015M3A9A5030735) of the Ministry of Science, ICT, and Future Planning through the National Research Foundation, Republic of Korea to HOY. This work was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2016R1D1A1A099) to S.C.

Compliance with Ethical Standards

The animal protocols used in this study were in accordance with the Korea Institute of Science and Technology Animal Care Committee guidelines.

Supplementary material

12035_2018_1023_MOESM1_ESM.docx (2.3 mb)
ESM 1 (DOCX 2344 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Natural Products Research CenterKorea Institute of Science and TechnologyGangneungRepublic of Korea
  2. 2.Department of PhysiologySungkyunkwan University School of MedicineSuwonRepublic of Korea
  3. 3.Division of Bio-Medical Science & Technology, KIST SchoolKorea University of Science and TechnologySeoulRepublic of Korea

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