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  • Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition. 21192972

    N-methyl-D-aspartate receptor (NMDAR) ontogeny and subunit expression are altered during developmental lead (Pb²+) exposure. However, it is unknown whether these changes occur at the synaptic or cellular level. Synaptic and extra-synaptic NMDARs have distinct cellular roles, thus, the effects of Pb²+ on NMDAR synaptic targeting may affect neuronal function. In this communication, we show that Pb²+ exposure during synaptogenesis in hippocampal neurons altered synaptic NMDAR composition, resulting in a decrease in NR2A-containing NMDARs at established synapses. Conversely, we observed increased targeting of the obligatory NR1 subunit of the NMDAR to the postsynaptic density (PSD) based on the increased colocalization with the postsynaptic protein PSD-95. This finding together with increased binding of the NR2B-subunit specific ligand [³H]-ifenprodil, suggests increased targeting of NR2B-NMDARs to dendritic spines as a result of Pb²+ exposure. During brain development, there is a shift of NR2B- to NR2A-containing NMDARs. Our findings suggest that Pb²+ exposure impairs or delays this developmental switch at the level of the synapse. Finally, we show that alter expression of NMDAR complexes in the dendritic spine is most likely due to NMDAR inhibition, as exposure to the NMDAR antagonist aminophosphonovaleric acid (APV) had similar effects as Pb²+ exposure. These data suggest that NMDAR inhibition by Pb²+ during synaptogensis alters NMDAR synapse development, which may have lasting consequences on downstream signaling.
    Document Type:
    Reference
    Product Catalog Number:
    AB1557P
    Product Catalog Name:
    Anti-NMDAR2B Antibody

  • Chronic lead exposure reduces doublecortin-expressing immature neurons in young adult guinea pig cerebral cortex. 22812564

    Chronic lead (Pb) poisoning remains an environmental risk especially for the pediatric population, and it may affect brain development. Immature neurons expressing doublecortin (DCX+) exist around cortical layer II in various mammals, including adult guinea pigs and humans. Using young adult guinea pigs as an experimental model, the present study explored if chronic Pb exposure affects cortical DCX + immature neurons and those around the subventricular and subgranular zones (SVZ, SGZ).Two month-old guinea pigs were treated with 0.2% lead acetate in drinking water for 2, 4 and 6 months. Blood Pb levels in these animals reached 10.27 ± 0.62, 16.25 ± 0.78 and 19.03 ± 0.86 μg/dL at the above time points, respectively, relative to ~3 μg/dL in vehicle controls. The density of DCX + neurons was significantly reduced around cortical layer II, SVZ and SGZ in Pb-treated animals surviving 4 and 6 months relative to controls. Bromodeoxyuridine (BrdU) pulse-chasing studies failed to find cellular colocalization of this DNA synthesis indicator in DCX + cells around layer II in Pb-treated and control animals. These cortical immature neurons were not found to coexist with active caspase-3 or Fluoro-Jade C labeling.Chronic Pb exposure can lead to significant reduction in the number of the immature neurons around cortical layer II and in the conventional neurogenic sites in young adult guinea pigs. No direct evidence could be identified to link the reduced cortical DCX expression with alteration in local neurogenesis or neuronal death.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Lead dysregulates serine/threonine protein phosphatases in human neurons. 21046238

    It is well established that lead (Pb) exposure in humans leads to learning and memory impairment. However, the biological and molecular mechanisms are still not clearly understood. When over activated, serine/threonine protein phosphatases are known to function as a constraint on learning and memory. Activation of these phosphatases can also result in cytoskeletal changes that will adversely affect learning and memory. We investigated the effects of Pb exposure on these phosphatases in primary cultures of human neurons. Neurons were exposed to physiologically relevant concentrations of Pb (5, 10, 20 and 40 ?g/dL) and total phosphatase and PP2A activities were determined in neuronal lysate using para-nitrophenyl phosphate (pNPP), and a PP2A-specific phosphopeptide as substrates. Expression of various serine/threonine phosphatases, tau and its phosphorylation state were determined by Western blot (WB) and immunocytochemistry (ICC). We found that the total phosphatase activity in the neuronal lysate was increased by 30-50% by all the concentrations of Pb tested. PP2A activity was increased by 5 ?g/dL Pb only. PP1 expression was increased (ranging from 25-50%) by 10, 20 and 40 ?g/dL of Pb. PP2B expression was increased substantially (up to 2.5-fold) by 10 ?g/dL Pb, whereas, higher concentrations did not show any effect. On the other hand, Pb (at all concentrations used) decreased expression of PP2A and PP5. Pb exposure induced substantial hyperphosphorylation of tau at serine 199/202 by 5 and 10 ?g/dL Pb, and Threonine 231 at higher doses. Expression of total tau was mostly unaffected by lead. Immunocytochemistry data confirmed the WB results of expression of PP1, PP2A, tau protein and the phosphorylation of tau. These results support our hypothesis that Pb exposure up regulates some of the serine/threonine phosphatases (PP1 and PP2B) that are known to impair memory formation, and suggest a novel mechanism of Pb neurotoxicity.
    Document Type:
    Reference
    Product Catalog Number:
    17-313
    Product Catalog Name:
    PP2A Immunoprecipitation Phosphatase Assay Kit

  • Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling. 20375082

    Lead (Pb(2+)) exposure is known to affect presynaptic neurotransmitter release in both in vivo and cell culture models. However, the precise mechanism by which Pb(2+) impairs neurotransmitter release remains unknown. In the current study, we show that Pb(2+) exposure during synaptogenesis in cultured hippocampal neurons produces the loss of synaptophysin (Syn) and synaptobrevin (Syb), two proteins involved in vesicular release. Pb(2+) exposure also increased the number of presynaptic contact sites. However, many of these putative presynaptic contact sites lack Soluble NSF attachment protein receptor complex proteins involved in vesicular exocytosis. Analysis of vesicular release using FM 1-43 dye confirmed that Pb(2+) exposure impaired vesicular release and reduced the number of fast-releasing sites. Because Pb(2+) is a potent N-methyl-D-aspartate receptor (NMDAR) antagonist, we tested the hypothesis that NMDAR inhibition may be producing the presynaptic effects. We show that NMDAR inhibition by aminophosphonovaleric acid mimics the presynaptic effects of Pb(2+) exposure. NMDAR activity has been linked to the signaling of the transsynaptic neurotrophin brain-derived neurotrophic factor (BDNF), and we observed that both the cellular expression of proBDNF and release of BDNF were decreased during the same period of Pb(2+) exposure. Furthermore, exogenous addition of BDNF rescued the presynaptic effects of Pb(2+). We suggest that the presynaptic deficits resulting from Pb(2+) exposure during synaptogenesis are mediated by disruption of NMDAR-dependent BDNF signaling.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice. 21703292

    Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤ 1, ≤ 10, ~25 and ~40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. 23246732

    Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood. Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status. Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine-binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus. Long Evans dams were fed chow with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and remained on the same diet through weaning (perinatal exposure group). Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group). All animals were euthanized on day 55 and hippocampi were removed. Western blot analyses showed significant effects of Pb exposure on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and modified by sex and developmental window of Pb exposure. These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases.
    Document Type:
    Reference
    Product Catalog Number:
    ABE171

  • H-CRRETAWAC-OH, a lead structure for the development of radiotracer targeting integrin α5β1? 25374888

    Imaging of angiogenic processes is of great interest in preclinical research as well as in clinical settings. The most commonly addressed target structure for imaging angiogenesis is the integrin α(v)β(3). Here we describe the synthesis and evaluation of [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH, a radiolabelled peptide designed to selectively target the integrin α(5)β(1). Conjugation of 4-nitrophenyl-(RS)-2-[(18)F]fluoropropionate provided [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH in high radiochemical purity (greater than 95%) and a radiochemical yield of approx. 55%. In vitro evaluation showed α(5)β(1) binding affinity in the nanomolar range, whereas affinity to α(v)β(3) and α(IIb)β(3) was greater than 50 μM. Cell uptake studies using human melanoma M21 (α(v)β(3)-positive and α(5)β(1)-negative), human melanoma M21-L (α(v)β(3)-negative and α(5)β(1)-negative), and human prostate carcinoma DU145 (α(v)β(3)-negative and α(5)β(1)-positive) confirmed receptor-specific binding. The radiotracer was stable in human serum and showed low protein binding. Biodistribution studies showed tumour uptake ranging from 2.5 to 3.5% ID/g between 30 and 120 min post-injection. However, blocking studies and studies using mice bearing α(5)β(1)-negative M21 tumours did not confirm receptor-specific uptake of [(18)F]FProp-Cys(*)-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys(*)-OH, although this radiopeptide revealed high affinity and substantial selectivity to α(5)β(1) in vitro. Further experiments are needed to study the in vivo metabolism of this peptide and to develop improved radiopeptide candidates suitable for PET imaging of α(5)β(1) expression in vivo.
    Document Type:
    Reference
    Product Catalog Number:
    MAB1976
    Product Catalog Name:
    Anti-Integrin αVβ3 Antibody, clone LM609