EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model

Wen-bin Wan; Lan Cao; Lu-mei Liu; Bill Kalionis; Chuan Chen; Xian-tao Tai; Ya-ming Li; Shi-jin Xia

doi:10.1371/journal.pone.0113126

EGb761 provides a protective effect against Aβ1-42 oligomer-induced cell damage and blood-brain barrier disruption in an in vitro bEnd.3 endothelial model

PLoS One. 2014 Nov 26;9(11):e113126. doi: 10.1371/journal.pone.0113126. eCollection 2014.

Authors

Wen-bin Wan¹, Lan Cao², Lu-mei Liu³, Bill Kalionis⁴, Chuan Chen⁵, Xian-tao Tai⁶, Ya-ming Li³, Shi-jin Xia⁷

Affiliations

¹ Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
² State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Geriatrics Department of Traditional Chinese Medicine, Huadong Hospital, Fudan University, Shanghai, China.
⁴ Department of Perinatal Medicine Pregnancy Research Centre and University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, VIC, Australia.
⁵ Shanghai Geriatric Institute of Chinese Medicine, Shanghai, China.
⁶ School of Acupuncture, Massage and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China.
⁷ Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, China.

Abstract

Alzheimer's disease (AD) is the most common form of senile dementia which is characterized by abnormal amyloid beta (Aβ) accumulation and deposition in brain parenchyma and cerebral capillaries, and leads to blood-brain barrier (BBB) disruption. Despite great progress in understanding the etiology of AD, the underlying pathogenic mechanism of BBB damage is still unclear, and no effective treatment has been devised. The standard Ginkgo biloba extract EGb761 has been widely used as a potential cognitive enhancer for the treatment of AD. However, the cellular mechanism underlying the effect remain to be clarified. In this study, we employed an immortalized endothelial cell line (bEnd.3) and incubation of Aβ(1-42) oligomer, to mimic a monolayer BBB model under conditions found in the AD brain. We investigated the effect of EGb761 on BBB and found that Aβ1-42 oligomer-induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS), were attenuated by treatment with EGb761. Moreover, treatment of the cells with EGb761 decreased BBB permeability and increased tight junction scaffold protein levels including ZO-1, Claudin-5 and Occludin. We also found that the Aβ(1-42) oligomer-induced upregulation of the receptor for advanced glycation end-products (RAGE), which mediates Aβ cytotoxicity and plays an essential role in AD progression, was significantly decreased by treatment with EGb761. To our knowledge, we provide the first direct in vitro evidence of an effect of EGb761 on the brain endothelium exposed to Aβ(1-42) oligomer, and on the expression of tight junction (TJ) scaffold proteins and RAGE. Our results provide a new insight into a possible mechanism of action of EGb761. This study provides a rational basis for the therapeutic application of EGb761 in the treatment of AD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / antagonists & inhibitors*
Amyloid beta-Peptides / pharmacology
Apoptosis / drug effects
Blood-Brain Barrier / cytology
Blood-Brain Barrier / drug effects
Cell Line, Transformed
Claudin-5 / genetics
Claudin-5 / metabolism
Endothelial Cells / cytology
Endothelial Cells / metabolism*
Gene Expression / drug effects
Ginkgo biloba
Humans
Models, Biological
Nootropic Agents / pharmacology*
Occludin / genetics
Occludin / metabolism
Peptide Fragments / antagonists & inhibitors*
Peptide Fragments / pharmacology
Plant Extracts / pharmacology*
Reactive Oxygen Species / agonists
Reactive Oxygen Species / antagonists & inhibitors*
Reactive Oxygen Species / metabolism
Receptor for Advanced Glycation End Products
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism
Tight Junctions / drug effects
Zonula Occludens-1 Protein / genetics
Zonula Occludens-1 Protein / metabolism

Substances

Amyloid beta-Peptides
CLDN5 protein, human
Claudin-5
Nootropic Agents
OCLN protein, human
Occludin
Peptide Fragments
Plant Extracts
Reactive Oxygen Species
Receptor for Advanced Glycation End Products
Receptors, Immunologic
TJP1 protein, human
Zonula Occludens-1 Protein
amyloid beta-protein (1-42)
Ginkgo biloba extract

Grants and funding

The authors gratefully acknowledge the financial support of this study by National Natural Science Foundation of China (Grant No. 81473739), and Shanghai Committee of Science and Technology, China (Grant No. 12401904500), YML received the funding, (http://www.nsfc.gov.cn/) and (http://www.stcsm.gov.cn/), respectively; by National Natural Science Foundation of China (Grant No. 31171129, Grant No. 81460748), SJX received the funding, (http://www.nsfc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.