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 Aβ1–42 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 Aβ1–42 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 Aβ1–42 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.
Highlights
Ginkgo biloba leaves are a type of medicinal herb and their extract has been shown to have neuroprotective properties and enhance cognitive functions [1,2]
Cerebrovascular changes leading to blood-brain barrier (BBB) leakiness have been associated with amyloid beta (Ab) deposition in the brains of Alzheimer’s disease (AD) individuals, and this may be involved in AD progression [13,14,15]
The results showed that incubation with various concentrations of EGb761 (25–200 mg/ml) in Opti-MEM did not lead to any significant changes in cell viability (Fig. 1A)
Summary
Ginkgo biloba leaves are a type of medicinal herb and their extract has been shown to have neuroprotective properties and enhance cognitive functions [1,2]. EGb761 has received significant attention as a potential cognitive enhancer for the treatment of Alzheimer’s disease (AD) [1,2,3,4]. Cerebrovascular changes leading to blood-brain barrier (BBB) leakiness have been associated with Ab deposition in the brains of AD individuals, and this may be involved in AD progression [13,14,15]. Despite great progress in understanding the etiology of AD, the process of deposition of Ab aggregates in cerebral capillaries and the brain is still poorly understood and the underlying pathogenic mechanisms of BBB leakage remain unclear.
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