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P3‐041: Drug Repositioning of XHC for Alzheimer’s Disease: Bace1 Promoter Repressing Activity of XHC
Author(s) -
Park Jin Su,
Cho Yoonsuk,
Kim HarkKyun,
Jung Gun Young,
Park Hee Jin,
Han Jihoon,
Baek Seung Hyun,
Bahn Gahee,
Choi Bo Youn,
Jo Dong-Gyu
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1699
Subject(s) - bace1 as , amyloid precursor protein secretase , amyloid precursor protein , amyloid (mycology) , drug , amyloid beta , pharmacology , proteolysis , extracellular , drug discovery , disease , biochemistry of alzheimer's disease , beta (programming language) , protease , chemistry , medicine , alzheimer's disease , biochemistry , enzyme , pathology , computer science , programming language
Background:Amyloid hypothesis postulated that exceed extracellular amyloid beta deposits are the fundamental cause of Alzheimer’s disease. Amyloid beta is produced by sequential proteolysis to amyloid beta precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. Another important phenomenon in AD patient is increased BACE1 expression. Methods:Our strategy is to find specific drugs reducing BACE1 expression rather than direct inhibition of BACE1. Using USA FDA approved drug library (Prestwick Chemical Library), we could discover putative therapeutic chemicals by cell based assay. Results:Among those candidates, XHC reduced the levels of BACE1 protein and mRNA in SH-SY5Y cells. A soluble APPb and C99 which are the products of BACE1 protease, were also decreased by treatment of XHC. We also confirmed that XHC could improve cognitive functions of 3XTg-AD mice. Decreased level of amyloid beta deposition and BACE1 expression also observed in XHC-treated AD mice. Conclusions: The fact that XHC is orally efficacious in AD animal models and is clinically safe to use make XHC an excellent candidate for advancement to clinical AD trials.