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
Source: PubMed


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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    • "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. "
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    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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    ABSTRACT: The desirable characteristics of lead -a malleable heavy metal resistant to corrosion -have resulted in its extensive use, especially in building construction, for the past several millen-nia. There is no known physiological relevant role for lead in the body; however, its harmful effects are numerous. Lead interferes with a variety of body processes and it is toxic to many organs and tissues. Like mercury, another heavy metal, lead is a potent neurotoxin that damages the nervous system and causes brain disorders. Although current lead usage has been minimized, lead exposure is still a risk because environmental lead is stable and no safe threshold for lead exposure has been established. Here, we review the current understand-ing of the effects of lead on the developing nervous system at the physiological, cellular, and molecular level. The effects of lead are particularly damaging to the developing nervous sys-tem, causing potentially irreversible learning and behavior deficits in children. Increased understanding of the deleterious effects of lead on the developing nervous system is vital to inform the safety guidelines associated with lead exposure.
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