Neuroprotective effect of the active components of three Chinese herbs on brain iron load in a mouse model of Alzheimer's disease.

Xian-Hui Dong,Yan Peng,Xi-Qing Chai,Tie-Mei Shao,Wei-Na Kong,Hong-Lin Xie,Wei-Juan Gao,Wen-Guo Yu

doi:10.3892/etm.2015.2234

Abstract

Alzheimer’s disease (AD) is a neurodegenerative brain disorder and the most common cause of dementia. New treatments for AD are required due to its increasing prevalence in aging populations. The present study evaluated the effects of the active components of Epimedium, Astragalus and Radix Puerariae on learning and memory impairment, β-amyloid (Aβ) reduction and brain iron load in an APPswe/PS1ΔE9 transgenic mouse model of AD. Increasing evidence indicates that a disturbance of normal iron homeostasis may contribute to the pathology of AD. However, the underlying mechanisms resulting in abnormal iron load in the AD brain remain unclear. It has been hypothesized that the brain iron load is influenced by the deregulation of certain proteins associated with brain iron metabolism, including divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1). The present study investigated the effects of the active components of Epimedium, Astragalus and Radix Puerariae on the expression levels of DMT1 and FPN1. The treatment with the active components reduced cognitive deficits, inhibited Aβ plaque accumulation, reversed Aβ burden and reduced the brain iron load in AD model mice. A significant increase was observed in the levels of DMT1-iron-responsive element (IRE) and DMT1-nonIRE in the hippocampus of the AD mouse brain, which was reduced by treatment with the active components. In addition, the levels of FPN1 were significantly reduced in the hippocampus of the AD mouse brain compared with those of control mice, and these levels were increased following treatment with the active components. Thus, the present study indicated that the active components of Epimedium, Astragalus and Radix Puerariae may exert a neuroprotective effect against AD by reducing iron overload in the AD brain and may provide a novel approach for the development of drugs for the treatment of AD.

Highlights

Alzheimer's disease (AD) is a neurodegenerative brain disorder and is the most common cause of dementia
It has been hypothesized that the brain iron load may be affected by the altered expression of certain brain iron metabolism‐associated proteins, including divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) [4]
The active component group consisted of APP/presenilin 1 (PS1) transgenic mice that received the active components of Astragalus, Radix Puerariae and Epimedium (120, 80 and 80 mg/kg, respectively), which was administered via oral gavage

Summary

Introduction

Alzheimer's disease (AD) is a neurodegenerative brain disorder and is the most common cause of dementia. It has been hypothesized that the brain iron load may be affected by the altered expression of certain brain iron metabolism‐associated proteins, including divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) [4]. DMT1 is a widely expressed protein, with 12 putative transmembrane‐spanning domains, and is responsible for the uptake of a broad range of divalent metal ions [6], including Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+ [7,8,9]. The four isoforms of DMT1 are distinguished through their mRNA transcripts, which vary at their 5'‐UTR and 3'‐UTR. Two of these four transcripts contain an IRE at the 3'‐end [10,11]. FPN1 is the sole exporter of iron and is responsible for iron absorption in the intestines, recycling of erythrocyte iron by macrophages and maternal delivery of iron to the fetus [12,13]

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