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

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

doi:10.3892/etm.2015.2234

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

Authors:
- Xian‑Hui Dong
- Wei‑Juan Gao
- Wei‑Na Kong
- Hong‑Lin Xie
- Yan Peng
- Tie‑Mei Shao
- Wen‑Guo Yu
- Xi‑Qing Chai
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Affiliations: Department of Anatomy, Chengde Medical University, Chengde, Hebei 067000, P.R. China, Department of Pathophysiology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China, Bioreactor and Protein Drug Research and Development Center of Hebei Universities, Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei 050000, P.R. China
Published online on: January 29, 2015 https://doi.org/10.3892/etm.2015.2234
Pages: 1319-1327

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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.

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1	Zhang J, Zhen YF, Pu-Bu-Ci-Ren, et al: Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res. 244:70–81. 2013. View Article : Google Scholar : PubMed/NCBI
2	El Tannir El Tayara N, Delatour B, Le Cudennec C, et al: Age-related evolution of amyloid burden, iron load, and MR relaxation times in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis. 22:199–208. 2006. View Article : Google Scholar
3	Crapper McLachlan DR, Dalton AJ, Kruck TP, et al: Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet. 337:1304–1308. 1991. View Article : Google Scholar : PubMed/NCBI
4	Xian-Hui D, Wei-Juan G, Tie-Mei S, et al: Age-related changes of brain iron load changes in the frontal cortex in APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. J Trace Elem Med Biol. Dec 3–2014.(Epub ahead of print).
5	Fleming MD, Trenor CC 3rd, Su MA, et al: Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 16:383–386. 1997.PubMed/NCBI
6	Li H, Li F, Sun H and Qian ZM: Membrane-inserted conformation of transmembrane domain 4 of divalent-metal transporter. Biochem J. 372:757–766. 2003. View Article : Google Scholar : PubMed/NCBI
7	Zhang LH, Wang X, Zheng ZH, et al: Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain. Neurobiol Aging. 31:74–87. 2010. View Article : Google Scholar
8	Gunshin H, Mackenzie B, Berger UV, et al: Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 388:482–488. 1997. View Article : Google Scholar : PubMed/NCBI
9	Erikson KM and Aschner M: Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter. Neurotoxicology. 27:125–130. 2006. View Article : Google Scholar
10	Lee PL, Gelbart T, West C, et al: The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis. 24:199–215. 1998. View Article : Google Scholar : PubMed/NCBI
11	Mackenzie B, Takanaga H, Hubert N, et al: Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J. 403:59–69. 2007. View Article : Google Scholar :
12	De Domenico I, Nemeth E, Nelson JM, et al: The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab. 8:146–156. 2008. View Article : Google Scholar : PubMed/NCBI
13	Donovan A, Lima CA, Pinkus JL, et al: The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 1:191–200. 2005. View Article : Google Scholar : PubMed/NCBI
14	Wan S, Hua Y, Keep RF, et al: Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage. Acta Neurochir Suppl. 96:199–202. 2006. View Article : Google Scholar : PubMed/NCBI
15	Hishikawa T, Ono S, Ogawa T, et al: Effects of deferoxamine-activated hypoxia-inducible factor-1 on the brainstem after subarachnoid hemorrhage in rats. Neurosurgery. 62:232–241. 2008. View Article : Google Scholar : PubMed/NCBI
16	Gao J, Inagaki Y and Liu Y: Research progress on flavonoids isolated from traditional Chinese medicine in treatment of Alzheimer’s disease. Intractable Rare Dis Res. 2:3–10. 2013.PubMed/NCBI
17	Liu XY, Zi H, Zheng HX, et al: Tissues distribution of Icariin and its metabolites in kidney of osteoporosis model rats. Zhongguo Shiyan Fangiixue Zazhi. 20:125–128. 2014.
18	Chen GH and Huang WF: Progress in pharmacological effects of compositions of Astragalus membranaceus. Zhongguo Xinyao Zazhi. 17:1482–1485. 2008.
19	Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 11:47–60. 1984. View Article : Google Scholar : PubMed/NCBI
20	Gu Y, Hua Y, Keep RF, et al: Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 40:2241–2243. 2009. View Article : Google Scholar : PubMed/NCBI
21	Yin C, Li S, Zhao W and Feng J: Brain imaging of mild cognitive impairment and Alzheimer’s disease. Neural Regen Res. 8:435–444. 2013.PubMed/NCBI
22	Blennow K, de Leon MJ and Zetterberg H: Alzheimer’s disease. Lancet. 368:387–403. 2006. View Article : Google Scholar : PubMed/NCBI
23	Imbimbo BP, Lombard J and Pomara N: Pathophysiology of Alzheimer’s disease. Neuroimaging Clin N Am. 15:727–753. 2005. View Article : Google Scholar
24	Nojima J, Maeda A, Aoki S, et al: Effect of rice-expressed amyloid β in the Tg2576 Alzheimer’s disease transgenic mouse model. Vaccine. 29:6252–6258. 2011. View Article : Google Scholar : PubMed/NCBI
25	Tang J, Wu L, Huang HL, et al: Back propagation artificial neural network for community Alzheimer’s disease screening in China. Neural Regen Res. 8:270–276. 2013.PubMed/NCBI
26	Guo C, Wang T, Zheng W, et al: Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 34(2): 562–75. 2013. View Article : Google Scholar
27	Overk CR, Perez SE, Ma C, et al: Sex steroid levels and AD-like pathology in 3xTgAD mice. J Neuroendocrinol. 25:131–144. 2013. View Article : Google Scholar
28	Marques SC, Lemos R, Ferreiro E, et al: Epigenetic regulation of BACE1 in Alzheimer’s disease patients and in transgenic mice. Neuroscience. 220:256–266. 2012. View Article : Google Scholar : PubMed/NCBI
29	Yang Y, Shiao C, Hemingway JF, et al: Suppressed retinal degeneration in aged wild type and APPswe/PS1ΔE9 mice by bone marrow transplantation. PLoS One. 8:e642462013. View Article : Google Scholar
30	Cheng D, Low JK, Logge W, et al: Novel behavioural characteristics of female APPSwe/PS1ΔE9 double transgenic mice. Behav Brain Res. 260:111–118. 2014. View Article : Google Scholar
31	Whitnall M and Richardson DR: Iron: a new target for pharmacological intervention in neurodegenerative diseases. Semin Pediatr Neurol. 13:186–197. 2006. View Article : Google Scholar : PubMed/NCBI
32	Guo C, Wang T, Zheng W, et al: Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 34:562–575. 2013. View Article : Google Scholar
33	Wu J, Bie B, Yang H, et al: Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. 34:791–804. 2013. View Article : Google Scholar
34	Han M, Liu Y, Tan Q, et al: Therapeutic efficacy of stemazole in a beta-amyloid injection rat model of Alzheimer’s disease. Eur J Pharmacol. 657:104–110. 2011. View Article : Google Scholar : PubMed/NCBI
35	Hardy J and Allsop D: Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci. 12:383–388. 1991. View Article : Google Scholar : PubMed/NCBI
36	Park MH, Lee JK, Choi S, et al: Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer’s disease mice. Brain Res. 1529:113–124. 2013. View Article : Google Scholar : PubMed/NCBI
37	Miller DL, Papayannopoulos IA, Styles J, et al: Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys. 301:41–52. 1993. View Article : Google Scholar : PubMed/NCBI
38	Delacourte A, Sergeant N, Champain D, et al: Nonoverlapping but synergetic tau and APP pathologies in sporadic Alzheimer’s disease. Neurology. 59:398–407. 2002. View Article : Google Scholar : PubMed/NCBI
39	Lue LF, Kuo YM, Roher AE, et al: Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol. 155:853–862. 1999. View Article : Google Scholar : PubMed/NCBI
40	Li S, Jin M, Koeglsperger T, et al: Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci. 31:6627–6638. 2011. View Article : Google Scholar : PubMed/NCBI
41	Masliah E, Mallory M, Alford M, et al: Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology. 56:127–129. 2001. View Article : Google Scholar : PubMed/NCBI
42	Sze CI, Troncoso JC, Kawas C, et al: Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol. 56:933–944. 1997. View Article : Google Scholar : PubMed/NCBI
43	Jomova K and Valko M: Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr Pharm Des. 17:3460–3473. 2011. View Article : Google Scholar : PubMed/NCBI
44	Huang X, Atwood CS, Moir RD, et al: Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer’s Abeta peptides. J Biol Inorg Chem. 9:954–960. 2004. View Article : Google Scholar : PubMed/NCBI
45	Liu G, Huang W, Moir RD, et al: Metal exposure and Alzheimer’s pathogenesis. J Struct Biol. 155:45–51. 2006. View Article : Google Scholar : PubMed/NCBI
46	Lovell MA, Robertson JD, Teesdale WJ, et al: Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci. 158:47–52. 1998. View Article : Google Scholar : PubMed/NCBI
47	Finefrock AE, Bush AI and Doraiswamy PM: Current status of metals as therapeutic targets in Alzheimer’s disease. J Am Geriatr Soc. 51:1143–1148. 2003. View Article : Google Scholar : PubMed/NCBI
48	Colangelo V, Schurr J, Ball MJ, et al: Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res. 70:462–473. 2002. View Article : Google Scholar : PubMed/NCBI
49	Zhang LH, Wang X, Stoltenberg M, et al: Abundant expression of zinc transporters in the amyloid plaques of Alzheimer’s disease brain. Brain Res Bull. 77:55–60. 2008. View Article : Google Scholar : PubMed/NCBI
50	Kawabata H, Germain RS, Vuong PT, et al: Transferrin receptor2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem. 275:16618–16625. 2000. View Article : Google Scholar : PubMed/NCBI
51	McKie AT, Marciani P, Rolfs A, et al: A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 5:299–309. 2000. View Article : Google Scholar : PubMed/NCBI
52	Abboud S and Haile DJ: A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 275:19906–19912. 2000. View Article : Google Scholar : PubMed/NCBI
53	Hellman NE and Gitlin JD: Ceruloplasmin metabolism and function. Annu Rev Nutr. 22:439–458. 2002. View Article : Google Scholar : PubMed/NCBI
54	Anderson GJ, Frazer DM, McKie AT and Vulpe CD: The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption. Blood Cells Mol Dis. 29:367–375. 2002. View Article : Google Scholar
55	Fleming RE and Sly WS: Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA. 98:8160–8162. 2001. View Article : Google Scholar : PubMed/NCBI
56	Krause A, Neitz S, Mägert HJ, et al: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480:147–150. 2000. View Article : Google Scholar : PubMed/NCBI
57	Shawki A and Mackenzie B: Interaction of calcium with the human divalent metal-ion transporter-1. Biochem Biophys Res Commun. 393:471–475. 2010. View Article : Google Scholar : PubMed/NCBI
58	Donovan A, Brownlie A, Zhou Y, et al: Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 403:776–781. 2000. View Article : Google Scholar : PubMed/NCBI
59	Anderson GJ and Vulpe CD: Mammalian iron transport. Cell Mol Life Sci. 66:3241–3261. 2009. View Article : Google Scholar : PubMed/NCBI
60	Ke Y, Chang YZ, Duan XL, et al: Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain. Neurobiol Aging. 26:739–748. 2005. View Article : Google Scholar : PubMed/NCBI