Lead-induced accumulation of β-amyloid in the choroid plexus: Role of low density lipoprotein receptor protein-1 and protein kinase C
School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.NeuroToxicology (Impact Factor: 3.38). 09/2010; 31(5):524-32. DOI: 10.1016/j.neuro.2010.05.004
The choroid plexus (CP), constituting the blood-cerebrospinal fluid barrier, has the capacity to remove beta-amyloid (Abeta) from the cerebrospinal fluid. Our previous work indicates that exposure to lead (Pb) results in Abeta accumulation in the CP by decreasing the expression of low density lipoprotein receptor protein-1 (LRP1), a protein involved in the transport and clearance of Abeta. The current study was designed to explore the relationship between Abeta accumulation, protein kinase C (PKC) activity, and LRP1 status in the CP following Pb exposure. Confocal microscopy revealed that LRP1 was primarily localized in the cytosol of the CP in control rats and migrated distinctly towards the apical surface and the microvilli following acute Pb exposure (27 mg Pb/kg, i.p., 24h). Co-immunostaining revealed a co-localization of both PKC-delta and LRP1 in the cytosol of control rats, with a distinct relocalization of both towards the apical membrane following Pb exposure. Preincubation of the tissues with PKC-delta inhibitor rottlerin (2 microM) prior to Pb exposure in vitro, resulted in abolishing the Pb-induced relocalization of LRP1 to the apical surface. Importantly, a significant elevation in intracellular Abeta levels (p<0.01) was observed in the cytosol of the CP following Pb exposure, which was abolished following preincubation with rottlerin. In addition, rottlerin caused a relocalization of Abeta from the cytosol to the nucleus in both Pb-treated and control CP tissues. Finally, co-immunoprecipitation studies revealed a strong protein-protein interaction between LRP1 and PKC-delta in the CP. These studies suggest that Pb exposure disrupts Abeta homeostasis at the CP, owing partly to a Pb-induced relocalization of LRP1 via PKC-delta.
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- "Cells' DNA, lipid bilayers and thiol compounds are prime targets of lead induced oxidative attack  . Recent findings have implicated Pb-induced ROS generation and long-term persistence of associated adverse effects with increased risk of developing late-onset diseases in exposed subjects   . Increased cancer and cardiovascular mortality was associated with lead exposure . "
ABSTRACT: Lead induced oxidative cellular damage and long-term persistence of associated adverse effects increases risk of late-onset diseases. CaNa2EDTA chelation is known to remove contaminating metals and to reduce free radical production. The objective was to investigate the impact of chelation therapy on modulation of lead induced cellular damage, restoration of altered enzyme activities and lipid homeostasis in peripherall blood of workers exposed to lead, by comparing the selected biomarkers obtained prior and after five-day CaNa2EDTA chelation intervention. The group of smelting factory workers diagnosed with lead intoxication and current lead exposure 5.8 ± 1.2 years were administered five-day CaNa2EDTA chelation. Elevated baseline activity of antioxidant enzymes Cu, Zn-SOD and CAT as well as depleted thiols and increased protein degradation products-carbonyl groups and nitrites, pointing to Pb induced oxidative damage, were restored toward normal values following the treatment. Lead showed inhibitor potency on both AChE and BChE in exposed workers, and chelation re-established the activity of BChE, while RBC AChE remained unaffected. Also, genotoxic effect of lead detected in peripheral blood lymphocytes was significantly decreased after therapy, exhibiting 18.9% DNA damage reduction. Administration of chelation reversed the depressed activity of serum PON 1 and significantly decreased lipid peroxidation detected by the post-chelation reduction of MDA levels. Lactate dehydrogenase LDH1-5 isoenzymes levels showed evident but no significant trend of restoring toward normal control values following chelation. CaNa2EDTA chelation ameliorates the alterations linked with Pb mediated oxidative stress, indicating possible benefits in reducing health risks associated with increased oxidative damage in lead exposed populations. Read my paper for free at: www.tandfonline.com/eprint/yc6rTaRCwEK2SBzzn9Mv/full
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- "More needs to be known about efflux transport in the basolateral membrane because this is the final step in disposing CNS-CSF Aβ into blood, thus protecting CP epithelium and ultimately the brain from Aβ toxicity. In acute Pb-toxicity model, the decreased expression of LRP1 in CP epithelium was associated, paradoxically, with increased Aβ in CP (Behl et al., 2010); however, CP Aβ efflux into blood was uncharacterized; a factor also affecting epithelial Aβ concentration. "
ABSTRACT: Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Ab) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: b-amyloid (Ab) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Ab in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Ab42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Ab transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Ab burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Ab) and diminished secretion of TTR (less neuroprotection against cortical Ab toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.
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