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Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

Carro, Eva, Spuch, Carlos, Trejo, Jose Luis, Antequera, Desiré, Torres-Aleman, Ignacio·2005·The Journal of Neuroscience
DOI 10.1523/jneurosci.2909-05.2005
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Abstract

The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid β (Aβ) by modulating transport/production of Aβ carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of Aβ carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Aβ and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimer's disease.

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Figure 1 Modulation of choroid plexus megalin. A , Photomicrograph, Megalin immunoreactivity (red) is highly abundant in rat and mouse choroid plexus (CP). Histograms, IGF-I levels in cerebellum of C57BL/6 mice were increased after exercise ( n = 3-4; * p < 0.05 vs sedentary mice by Student's t test). Error bars represent SEM. Blot, Exercised mice show significantly increased megalin levels in choroid plexus, whereas levels of IGF-IRs in choroid plexus remained unchanged. A representative blot is shown. Quantitative densitometry showed a more than twofold increase in megalin levels ( n = 5; p < 0.05 vs sedentary mice by Student's t test). Scale bars, 20 𝛍 m. B , Injection of IGF-I (10 𝛍 g) into the carotid of adult Wistar rats stimulates auto-phosphorylation of IGF-IRs in choroid plexus as well as phosphorylation of Akt, a canonical downstream signal of IGF-I. Levels of IGF-IRs and Akt remain unchanged ( n = 4). p, Phosphorylated. C , Exposure of rat choroid plexus epithelial cells to IGF-I (100 nM) resulted in significantly increased levels of megalin 24 h later. A representative blot is shown. Levels of megalin were normalized to PI3K levels in choroid plexus. Quantitative densitometry showed a twofold increase ( n = 5; p < 0.05 vs control).
Figure 1 Modulation of choroid plexus megalin. A , Photomicrograph, Megalin immunoreactivity (red) is highly abundant in rat and mouse choroid plexus (CP). Histograms, IGF-I levels in cerebellum of C57BL/6 mice were increased after exercise ( n = 3-4; * p < 0.05 vs sedentary mice by Student's t test). Error bars represent SEM. Blot, Exercised mice show significantly increased megalin levels in choroid plexus, whereas levels of IGF-IRs in choroid plexus remained unchanged. A representative blot is shown. Quantitative densitometry showed a more than twofold increase in megalin levels ( n = 5; p < 0.05 vs sedentary mice by Student's t test). Scale bars, 20 𝛍 m. B , Injection of IGF-I (10 𝛍 g) into the carotid of adult Wistar rats stimulates auto-phosphorylation of IGF-IRs in choroid plexus as well as phosphorylation of Akt, a canonical downstream signal of IGF-I. Levels of IGF-IRs and Akt remain unchanged ( n = 4). p, Phosphorylated. C , Exposure of rat choroid plexus epithelial cells to IGF-I (100 nM) resulted in significantly increased levels of megalin 24 h later. A representative blot is shown. Levels of megalin were normalized to PI3K levels in choroid plexus. Quantitative densitometry showed a twofold increase ( n = 5; p < 0.05 vs control).CC-BY-NC-SA · From the PDF
Figure 2 Megalin is involved in IGF-I-induced transport of A 𝛃 through choroid plexus. A , Blots, Immunoprecipitation with anti-megalin of rat choroid plexus cell extracts followed by blotting with respective antibodies revealed association of megalin with exogenously added A 𝛃 , digoxigenin-labeled albumin (Dig-Alb), and TTR. No bands are seen in control cultures treated with vehicle. Immunoprecipitation with nonspecific serum [normal rabbit serum (NRS)] showed no unspecific association of A 𝛃 . Reciprocal coimmunoprecipitationconfirmedtheseinteractions(datanotshown,butseeFig.3 A ). Representative blots are shown ( n = 4). Micrographs, Megalin colocalizes with exogenously added A 𝛃 and the A 𝛃 carriers albumin (Dig-Alb) and TTR in choroid plexus cultures. Confocal analysis shows merging of immunostaining signals. Scale bars, 10 𝛍 m. IP, Immunoprecipitation. B , Albumin and TTR bind to A 𝛃 in choroid plexus cultures. Choroid plexus cultures were treated with either TTR plus A 𝛃 or Dig-Alb plus A 𝛃 and cell lysates immunoprecipitated with either anti-TTR (top blots) or anti-digoxigenin and blotted with anti-A 𝛃 . Duplicate treatments are shown ( n = 4). C , Levels of choroid plexus megalin in rats are modified by viral expression of megalin siRNA (top blot) or miniMegalin (bottom blot). Note that levels of the unrelated protein PI3Kp85 remain undisturbed after expression of siMegalin, suggesting specificity of RNA interference. Two animals per group are shown ( n = 6). D , In vitro double-chamber well used to mimic the blood (lower chamber)-CSF (upper chamber) interface. Choroid plexus epithelial cells weregrownintheflooroftheuppercompartmentontopofaporousmembrane.Cellswereinfectedwitheitheremptyvirus(HIV)orHIV vectorexpressingeithersiRNAmegalinorminiMegalin.IGF-Iwasaddedtothelowerchamber,whereasA 𝛃 and/oritscarrierswereadded intheupperchamber. E , In HIV-infectedratcells,IGF-IpromotestranslocationofA 𝛃 fromtheuppertothelowercompartment.Thiseffect is blocked in cells infected with megalin siRNA (2 replicates are shown in siMegalin-treated cultures; n = 4). F , siMegalin also blocks translocationofalbumininducedbyIGF-I( n = 4). G , H , IncreasedlevelsofmegalinafterinfectionofcellswithHIV-miniMegalinenhances IGF-I-induced transport of A 𝛃 ( G ) and albumin ( H ) across rat choroid plexus epithelial cells. Representative blots are shown in duplicate wells. At least three independent experiments were run for each condition.
Figure 2 Megalin is involved in IGF-I-induced transport of A 𝛃 through choroid plexus. A , Blots, Immunoprecipitation with anti-megalin of rat choroid plexus cell extracts followed by blotting with respective antibodies revealed association of megalin with exogenously added A 𝛃 , digoxigenin-labeled albumin (Dig-Alb), and TTR. No bands are seen in control cultures treated with vehicle. Immunoprecipitation with nonspecific serum [normal rabbit serum (NRS)] showed no unspecific association of A 𝛃 . Reciprocal coimmunoprecipitationconfirmedtheseinteractions(datanotshown,butseeFig.3 A ). Representative blots are shown ( n = 4). Micrographs, Megalin colocalizes with exogenously added A 𝛃 and the A 𝛃 carriers albumin (Dig-Alb) and TTR in choroid plexus cultures. Confocal analysis shows merging of immunostaining signals. Scale bars, 10 𝛍 m. IP, Immunoprecipitation. B , Albumin and TTR bind to A 𝛃 in choroid plexus cultures. Choroid plexus cultures were treated with either TTR plus A 𝛃 or Dig-Alb plus A 𝛃 and cell lysates immunoprecipitated with either anti-TTR (top blots) or anti-digoxigenin and blotted with anti-A 𝛃 . Duplicate treatments are shown ( n = 4). C , Levels of choroid plexus megalin in rats are modified by viral expression of megalin siRNA (top blot) or miniMegalin (bottom blot). Note that levels of the unrelated protein PI3Kp85 remain undisturbed after expression of siMegalin, suggesting specificity of RNA interference. Two animals per group are shown ( n = 6). D , In vitro double-chamber well used to mimic the blood (lower chamber)-CSF (upper chamber) interface. Choroid plexus epithelial cells weregrownintheflooroftheuppercompartmentontopofaporousmembrane.Cellswereinfectedwitheitheremptyvirus(HIV)orHIV vectorexpressingeithersiRNAmegalinorminiMegalin.IGF-Iwasaddedtothelowerchamber,whereasA 𝛃 and/oritscarrierswereadded intheupperchamber. E , In HIV-infectedratcells,IGF-IpromotestranslocationofA 𝛃 fromtheuppertothelowercompartment.Thiseffect is blocked in cells infected with megalin siRNA (2 replicates are shown in siMegalin-treated cultures; n = 4). F , siMegalin also blocks translocationofalbumininducedbyIGF-I( n = 4). G , H , IncreasedlevelsofmegalinafterinfectionofcellswithHIV-miniMegalinenhances IGF-I-induced transport of A 𝛃 ( G ) and albumin ( H ) across rat choroid plexus epithelial cells. Representative blots are shown in duplicate wells. At least three independent experiments were run for each condition.CC-BY-NC-SA · From the PDF
Image 3
CC-BY-NC-SA · From the PDF
Image 4
CC-BY-NC-SA · From the PDF
Figure 5 Transport of IGF-I across the choroid plexus. A , Megalin in rat choroid plexus cells interacts with IGF-I. Blots, Reciprocal coimmunoprecipitation of megalin with IGF-I after adding the latter to choroid plexus cultures. Photomicrographs, Megalin (green) and IGF-I (red) colocalize in cultured choroid plexus epithelial cells. Scale bar, 10 𝛍 m. B , Rat choroid plexus cells expressing siMegalin translocate significantly less IGF-I from the lower to the upper culture chamber (see Fig. 1 E ). ** p < 0.01 versus HIV-infected cells by Student's t test. C , When rat choroid plexus cells express miniMegalin, the amount of translocated IGF-I is significantly increased. ** p < 0.01 by Student's t test. D , Rats infected with HIV-siMeg in the choroid plexus translocate significantly less Dig-IGF-I from the blood into the CSF. Representative blot and quantitative histograms are shown. * p < 0.05 versus HIV-infected rats by Student's t test ( n = 4). E , In rats expressing siMeg in the choroid plexus, intracarotid injection of IGF-I (10 𝛍 g per rat) results in significantly lower stimulation of Akt in brain parenchyma (hippocampus) 1 h later. Representative blots and quantitation histograms are shown. Total Akt remained unchanged. F , Rats expressing a KR IGF-IR in choroid plexus (HIV-KR rats) did not translocate Dig-IGF-I from the blood into the CSF. The blot shows Dig-IGF-I in CSF of HIV (control) and HIV-KR rats. Two rats per treatment are shown ( n = 5). G , Megalin is not required for IGF-Iinduced activation of Akt in rat choroid plexus. After infection of choroid plexus with HIV-siMeg, intracarotidIGF-IisstillabletostimulatephosphorylationofAktinchoroidplexus. H , Inhibition of PKC withbisindolylamine(Bis),butnotofPI3K/Aktwithwortmannin(Wort)orMAPKwithPD98059(PD), abrogates passage of Dig-IGF-I across a rat choroid plexus epithelial monolayer. Representative blots are shown. At least three independent in vitro experimentswererunforeachcondition.IP,Immunoprecipitation; siMeg, siMegalin; miniMeg, miniMegalin; p, phosphorylated.
Figure 5 Transport of IGF-I across the choroid plexus. A , Megalin in rat choroid plexus cells interacts with IGF-I. Blots, Reciprocal coimmunoprecipitation of megalin with IGF-I after adding the latter to choroid plexus cultures. Photomicrographs, Megalin (green) and IGF-I (red) colocalize in cultured choroid plexus epithelial cells. Scale bar, 10 𝛍 m. B , Rat choroid plexus cells expressing siMegalin translocate significantly less IGF-I from the lower to the upper culture chamber (see Fig. 1 E ). ** p < 0.01 versus HIV-infected cells by Student's t test. C , When rat choroid plexus cells express miniMegalin, the amount of translocated IGF-I is significantly increased. ** p < 0.01 by Student's t test. D , Rats infected with HIV-siMeg in the choroid plexus translocate significantly less Dig-IGF-I from the blood into the CSF. Representative blot and quantitative histograms are shown. * p < 0.05 versus HIV-infected rats by Student's t test ( n = 4). E , In rats expressing siMeg in the choroid plexus, intracarotid injection of IGF-I (10 𝛍 g per rat) results in significantly lower stimulation of Akt in brain parenchyma (hippocampus) 1 h later. Representative blots and quantitation histograms are shown. Total Akt remained unchanged. F , Rats expressing a KR IGF-IR in choroid plexus (HIV-KR rats) did not translocate Dig-IGF-I from the blood into the CSF. The blot shows Dig-IGF-I in CSF of HIV (control) and HIV-KR rats. Two rats per treatment are shown ( n = 5). G , Megalin is not required for IGF-Iinduced activation of Akt in rat choroid plexus. After infection of choroid plexus with HIV-siMeg, intracarotidIGF-IisstillabletostimulatephosphorylationofAktinchoroidplexus. H , Inhibition of PKC withbisindolylamine(Bis),butnotofPI3K/Aktwithwortmannin(Wort)orMAPKwithPD98059(PD), abrogates passage of Dig-IGF-I across a rat choroid plexus epithelial monolayer. Representative blots are shown. At least three independent in vitro experimentswererunforeachcondition.IP,Immunoprecipitation; siMeg, siMegalin; miniMeg, miniMegalin; p, phosphorylated.CC-BY-NC-SA · From the PDF
Figure 6 Role of megalin in choroid plexus. A , HIV-directed expression of miniMegalin (miniMeg) in choroid plexus of old rats resultsinincreasedmegalinlevels6monthsafterinjection,comparedwithHIV-injectedcontrols.Representativeblotisshown( n = 4). B , Oldratshavedecreasedmegalincontentinchoroidplexuscomparedwithadultanimals.Representativeblotandquantitationhistograms. ** p < 0.01versusadultratsbyStudent's t test ( n = 4). Error bars represent SEM. C , Hpf-tau deposits (red) within the pyramidal cell layer ofthehippocampusindifferentrodentmodelsofcognitivedeteriorationaftermodulationofmegalinlevelsinchoroidplexus.Neuronsare stained with calbindin (green). Ca , Cb , Hpf-tau staining, readily detectable in aged rats (30 months of age), is less prominent in aged rats expressing miniMeg in choroid plexus for 6 months. The left inset shows magnification of deposits in Ca . Cc , Cf , Ci , Scattered Hpf-tau deposits in APP/PS1 mice become more apparent after reduction of megalin levels with siMeg ( Cf ), whereas they are not substantially modified after miniMeg expression ( Ci ). The right inset shows magnification of deposits in Cf . Cd , Ce , LID mice have low levels of Hpf-tau deposits that disappear after miniMeg expression for 3 months. The right inset shows magnification of small deposits in Cd . Cg , Ch , Injection of HIV-siMeg to adult rats resulted in the appearance of scattered Hpf-tau deposits in the hippocampus. The inset in Ch shows magnificationofthedeposits.Representativehippocampalsectionsareshown.ChangesinHpf-taulevelswerequantifiedbyWesternblot (see Results). Control animals received void HIV vector intracerebroventricular injections in all cases. Scale bar, 20 𝛍 m. min Meg, miniMegalin;siMeg,siMegalin. D , FunctionalinteractionsbetweenserumIGF-Iandchoroidplexusmegalin.SerumIGF-Istimulatesitsreceptor at epithelial choroid plexus cells to induce its own transport across the cell via megalin. Serum IGF-I also enhances transport by megalin of A 𝛃 complexed with its carriers from the CSF to the blood through a caveolin-dependent endocytic pathway involving IGF-I-induced decouplingofDab2tomegalin.IGF-IrequiresPKCactivity,bothtofavortransportofA 𝛃 /carriercomplexesaswellastobetransporteditself bymegalin. Whether megalin binds IGF-I bound to the IGF-I receptor or free IGF-I requires additional analysis.
Figure 6 Role of megalin in choroid plexus. A , HIV-directed expression of miniMegalin (miniMeg) in choroid plexus of old rats resultsinincreasedmegalinlevels6monthsafterinjection,comparedwithHIV-injectedcontrols.Representativeblotisshown( n = 4). B , Oldratshavedecreasedmegalincontentinchoroidplexuscomparedwithadultanimals.Representativeblotandquantitationhistograms. ** p < 0.01versusadultratsbyStudent's t test ( n = 4). Error bars represent SEM. C , Hpf-tau deposits (red) within the pyramidal cell layer ofthehippocampusindifferentrodentmodelsofcognitivedeteriorationaftermodulationofmegalinlevelsinchoroidplexus.Neuronsare stained with calbindin (green). Ca , Cb , Hpf-tau staining, readily detectable in aged rats (30 months of age), is less prominent in aged rats expressing miniMeg in choroid plexus for 6 months. The left inset shows magnification of deposits in Ca . Cc , Cf , Ci , Scattered Hpf-tau deposits in APP/PS1 mice become more apparent after reduction of megalin levels with siMeg ( Cf ), whereas they are not substantially modified after miniMeg expression ( Ci ). The right inset shows magnification of deposits in Cf . Cd , Ce , LID mice have low levels of Hpf-tau deposits that disappear after miniMeg expression for 3 months. The right inset shows magnification of small deposits in Cd . Cg , Ch , Injection of HIV-siMeg to adult rats resulted in the appearance of scattered Hpf-tau deposits in the hippocampus. The inset in Ch shows magnificationofthedeposits.Representativehippocampalsectionsareshown.ChangesinHpf-taulevelswerequantifiedbyWesternblot (see Results). Control animals received void HIV vector intracerebroventricular injections in all cases. Scale bar, 20 𝛍 m. min Meg, miniMegalin;siMeg,siMegalin. D , FunctionalinteractionsbetweenserumIGF-Iandchoroidplexusmegalin.SerumIGF-Istimulatesitsreceptor at epithelial choroid plexus cells to induce its own transport across the cell via megalin. Serum IGF-I also enhances transport by megalin of A 𝛃 complexed with its carriers from the CSF to the blood through a caveolin-dependent endocytic pathway involving IGF-I-induced decouplingofDab2tomegalin.IGF-IrequiresPKCactivity,bothtofavortransportofA 𝛃 /carriercomplexesaswellastobetransporteditself bymegalin. Whether megalin binds IGF-I bound to the IGF-I receptor or free IGF-I requires additional analysis.CC-BY-NC-SA · From the PDF

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Authors
Carro, E., Spuch, C., Trejo, J. L., Antequera, D., & Torres-Aleman, I.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2005-11-23
Volume
25
Issue
47
Pages
10884-10893
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.2909-05.2005
Cited by
177
References
3
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)

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