Lead exposure increases levels of β-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice

Gu, Huiying; Wei, Xing; Monnot, Andrew D.; Fontanilla, Christine V.; Behl, Mamta; Farlow, Martin R.; Zheng, Wei; Du, Yansheng

doi:10.1016/j.neulet.2010.12.017

Cited by 58 publications

(44 citation statements)

References 31 publications

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“…U.S. Department of Health and Human Services and Environmental Protection Agency (EPA) have listed Pb compounds to be carcinogens, neurotoxicant, and neurodevelopmental toxicant (UNEP, 2006; IARC, 2006). Recent epidemiologic studies have also linked Pb exposure to the declined cognition (Bakulski et al, 2012) and the etiology of Alzheimer’s disease (Gu et al, 2011, 2012; Schwartz et al 2010; Stewart et al, 2006). Main sources of Pb exposure in the general population are food, water and airborne particulate (smoke included) (Forte et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

Zhang

Pan

et al. 2015

Environmental Research

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Baseline blood concentrations of metals are important references for monitoring metal exposure in environmental and occupational settings. The purpose of this study was to determine the blood levels of manganese (Mn), copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) among the residents (aged 12–60 years old) living in the suburb southwest of Beijing in China and to compare the outcomes with reported values in various developed countries. Blood samples were collected from 648 subjects from March 2009 to February 2010. Metal concentrations in the whole blood were determined by ICP-MS. The geometric means of blood levels of Mn, Cu, Zn, Pb and Cd were 11.4, 802.4, 4665, 42.6, and 0.68 μg/L, respectively. Male subjects had higher blood Pb than the females, while the females had higher blood Mn and Cu than the males. There was no gender difference for blood Cd and Zn. Smokers had higher blood Cu, Zn, and Cd than nonsmokers. There were significant age-related differences in blood levels of all metals studied; subjects in the 17–30 age group had higher blood levels of Mn, Pb, Cu, and Zn, while those in the 46–60 age group had higher Cd than the other age groups. A remarkably lower blood level of Cu and Zn in this population as compared with residents of other developed countries was noticed. Based on the current study, the normal reference ranges for the blood Mn were estimated to be 5.80–25.2 μ/L; for blood Cu, 541–1475 μ/L; for blood Zn, 2349–9492 μ/L; for blood Pb, <100 μ/L; and for blood Cd, <5.30 μ/L in the general population living in Beijing suburbs.

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Section: Discussionmentioning

confidence: 99%

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

Zhang

Pan

et al. 2015

Environmental Research

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“…An amyloid precursor protein (AβPP) transgenic mouse model overexpressing human AβPP with a mutation (V717F) that causes an autosomal dominant form of familial AD was utilized (Gu et al, 2011). In this study, 3 month old mice showed high levels of human Aβ protein in brains without having plaques, which was consistent to previous reports demonstrating these mice had an age-related accumulation of Aβ plaques in brains starting from 6 months of age (Bales et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

“…Since the CP is in direct continuity with the cerebral interstitial fluid (ISF) and the CSF, Aβ in the brains extracellular space can freely enter into the CSF. Immunoreactive Aβ and its precursor protein AβPP in the CP (Sasaki et al, 1997, Crossgrove et al, 2007) suggests that the CP may be involved in the brains Aβ clearance (Crossgrove et al, 2005, Behl et al, 2009a, Gu et al, 2011). Thus, it is interesting to explore the role of the BCB in the brain Aβ clearance and IVIG-induced efflux of Aβ from brains.…”

Section: Introductionmentioning

confidence: 99%

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The role of choroid plexus in IVIG-induced beta-amyloid clearance

Zhong

Jiang

et al. 2014

Neuroscience

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We have shown that intravenous immunoglobulin (IVIG) contains anti-Aβ autoantibodies and IVIG could induce beta amyloid (Aβ) efflux from cerebrospinal fluid (CSF) to blood in both Multiple Sclerosis (MS) and Alzheimer disease (AD) patients. However, the molecular mechanism underlying IVIG-induced Aβ efflux remains unclear. In this study, we used amyloid precursor protein (AβPP) transgenic mice to investigate if the IVIG could induce efflux of Aβ from the brain and whether low-density lipoprotein receptor-related protein-1 (LRP1), a hypothetic Aβ transporter in blood-cerebrospinal fluid barrier (BCB); could mediate this clearance process. We currently provide strong evidence to demonstrate that IVIG could reduce brain Aβ levels by pulling Aβ into the blood system in AβPP transgenic mice. In the mechanistic study, IVIG could induce Aβ efflux through the in-vitro BCB membrane formed by cultured BCB epithelial cells. Both RAP (receptor-associated protein; a functional inhibitor of LRP1), and LRP1 siRNA were able to significantly inhibit the Aβ efflux. Should Aβ prove to be the underlying cause of AD, our results strongly suggest that IVIG could be beneficial in the therapy for Alzheimer's disease (AD) by inducing efflux of Aβ from the brain through the LRP1 in the BCB.

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“…To date, the expression of many transporters/receptors and IDE on the choroid plexus and the ependymal cells has been reported, as presented in Table 1. Furthermore, the contributions of LRP1 (Behl Fujiyoshi et al 2011;Gu et al 2011), LRP2 (Zlokovic et al 1996Carro et al 2005) and IDE (Behl et al 2009) to Aβ clearance in the choroid plexus have been demonstrated. The expression of LRP1 was increased in the CP of aged rats and AD mice; that of LRP2 was decreased in the CP of aged humans, aged rodents and AD mice; and that of ABCB1 (P-gp) was increased in the CP of aged rats, implying the enhancement and/or compensatory effect on Aβ clearance from CSF at the BCSFB with aging and amyloid burden (Carro et al 2005;Johanson et al 2006;Dietrich et al 2008;Pascale et al 2011;González-Marrero et al 2015).…”

Section: Introductionmentioning

confidence: 96%

Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain

Matsumoto

Chiba

Fujihara

et al. 2015

Histochem Cell Biol

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A large number of previous reports have focused on the transport of amyloid-β peptides through cerebral endothelial cells via the blood-brain barrier, while fewer reports have mentioned the transport through the choroid plexus epithelium via the blood-cerebrospinal fluid barrier. Concrete roles of these two pathways remain to be clarified. In this study, we immunohistochemically examined the expression of transporters/receptors that are supposed to be related to the clearance of amyloid-β peptides in the choroid plexus epithelium, the ventricular ependymal cells and the brain microvessels, using seven autopsied human brains. In the choroid plexus epithelium, immunoreactivity for low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), LRP2, formylpeptide receptor-like 1 (FPRL1), ATP-binding cassette (ABC) transporter-A1 (ABCA1), ABCC1 and ABCG4 was seen in 7 of 7 brains, while that for ABCB1, ABCG2, RAGE and CD36 was seen in 0-2 brains. In the ventricular ependymal cells, immunoreactivity for CD36, LDLR, LRP1, LRP2, FPRL1, ABCA1, ABCC1 and ABCG4 was seen in 6-7 brains, while that for ABCB1, ABCG2 and RAGE was seen in 0-1 brain. Immunoreactivity for insulin-degrading enzyme (IDE) was seen in three and four brains in the choroid plexus epithelium and the ventricular ependymal cells, respectively. In addition, immunoreactivity for LDLR, ABCB1 and ABCG2 was seen in over 40 % of the microvessels (all seven brains), and that for FPRL1, ABCA1, ABCC1 and RAGE was seen in over 5 % of the microvessels (4-6 brains), while that for CD36, IDE, LRP1, LRP2 and ABCG4 was seen in less than 5 % of the microvessels (0-2 brains). These findings may suggest that these multiple transporters/receptors and IDE expressed on the choroid plexus epithelium, ventricular ependymal cells and brain microvessels complementarily or cooperatively contribute to the clearance of amyloid-β peptides from the brain.

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Lead exposure increases levels of β-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice

Cited by 58 publications

References 31 publications

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

The role of choroid plexus in IVIG-induced beta-amyloid clearance

Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain

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