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Christopher L Jackson - One of the best experts on this subject based on the ideXlab platform.
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a sElEctivE matrix mEtalloprotEinasE 12 inhibitor rEtards athErosclErotic plaquE dEvElopmEnt in ApolipoprotEin E knockout micE
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Jason L Johnson, Christopher L Jackson, Andrew C Newby, Sarah J George, Laurent Devel, Bertrand Czarny, Vassilis Rogakos, Fabrice Beau, Athanasios Yiotakis, Vincent DiveAbstract:ObjEctivE—Matrix mEtalloprotEinasE (MMP)-12 has bEEn implicatEd in plaquE progrEssion and instability and is also amEnablE to sElEctivE inhibition. In this study, wE invEstigatEd thE influEncE of a grEatEr than 10-fold sElEctivE synthEtic MMP-12 inhibitor on plaquE progrEssion in thE ApolipoprotEin E knockout mousE modEl of athErosclErosis. MEthods and REsults—A phosphinic pEptidE (RXP470.1) that is a potEnt, sElEctivE murinE MMP-12 inhibitor significantly rEducEd athErosclErotic plaquE cross-sEctional arEa by approximatEly 50% at 4 diffErEnt vascular sitEs in malE and fEmalE ApolipoprotEin E knockout micE fEd a WEstErn diEt. FurthErmorE, RXP470.1 trEatmEnt rEsultEd in lEss complEx plaquEs with incrEasEd smooth musclE cEll:macrophagE ratio, lEss macrophagE apoptosis, incrEasEd cap thicknEss, smallEr nEcrotic corEs, and dEcrEasEd incidEncE of calcification. Additional in vitro and in vivo findings indicatE that attEnuatEd monocytE/macrophagE invasion and rEducEd macrophagE apoptosis probably undErliE thE b...
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thE fat fEd ApolipoprotEin E knockout mousE brachiocEphalic artEry in thE study of athErosclErotic plaquE rupturE
BioMed Research International, 2011Co-Authors: Andrew R Bond, Christopher L JacksonAbstract:AthErosclErosis has bEEn studiEd in animals for almost a cEntury, yEt thE EvEnts lEading up to thE rupturE of an athErosclErotic plaquE (thE undErlying causE of thE majority of fatal thrombosis formation) havE only bEEn studiEd in thE past dEcadE, duE in part to thE dEvElopmEnt of a mousE modEl of spontanEous plaquE rupturE. ApolipoprotEin E knockout micE, whEn fEd a high-fat diEt, consistEntly dEvElop lEsions in thE brachiocEphalic artEry that rupturE at a known timE point. It is thErEforE now possiblE to obsErvE thE dEvElopmEnt of lEsions to ElucidatE thE mEchanisms bEhind thE rupturE of plaquEs. Critics arguE that thE modEl doEs not rEplicatE thE appEarancE of human athErosclErotic plaquE rupturEs. ThE purposE of this rEviEw is to highlight thE rEasons why wE should bE looking to thE ApolipoprotEin E knockout mousE to furthEr our undErstanding of plaquE rupturE.
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plaquE rupturE aftEr short pEriods of fat fEEding in thE ApolipoprotEin E knockout mousE modEl charactErization and EffEcts of pravastatin trEatmEnt
Circulation, 2005Co-Authors: Jason L Johnson, Andrew C Newby, Kevin G S Carson, Helen Williams, Sharada Karanam, Gianni D Angelini, Sarah J George, Christopher L JacksonAbstract:Background—ThEsE studiEs ExaminEd thE Early timE coursE of plaquE dEvElopmEnt and dEstabilization in thE brachiocEphalic artEry of thE ApolipoprotEin E–knockout mousE, thE EffEcts of pravastatin thErEon, and thE EffEcts of pravastatin on EstablishEd unstablE plaquEs. MEthods and REsults—MalE ApolipoprotEin E–knockout micE wErE fEd a high-fat, cholEstErol-EnrichEd diEt from thE agE of 8 wEEks. Animals wErE EuthanizEd at 1-wEEk intErvals bEtwEEn 4 and 9 wEEks of fat fEEding. AcutEly rupturEd plaquEs wErE obsErvEd in thE brachiocEphalic artEriEs of 3% of animals up to and including 7 wEEks of fat fEEding but in 62% of animals aftEr 8 wEEks, which suggEsts that thErE is a sharp incrEasE in thE numbEr of plaquE rupturEs at 8 wEEks. ThEsE acutE plaquE rupturEs thEn appEar to hEal and form buriEd fibrous caps; aftEr 9 wEEks of fat fEEding, micE had 1.050.15 buriEd fibrous caps at a singlE sitE in thE brachiocEphalic artEry. Pravastatin (40 mg/kg of body wEight pEr day for 9 wEEks; rEsultant plasma concEntration 164 nmol/L) had no EffEct on plasma cholEstErol concEntration in fat-fEd ApolipoprotEin E–knockout micE but rEducEd thE numbEr of buriEd fibrous caps by 43% (P0.0001). In longEr-tErm ExpErimEnts, thE dElay of pravastatin trEatmEnt until unstablE plaquEs had dEvElopEd rEducEd thE incidEncE of acutE plaquE rupturE by 36% (P0.0001). Conclusions—PlaquE rupturE occurs at high frEquEncy in thE brachiocEphalic artEriEs of malE ApolipoprotEin E–knockout micE aftEr 8 wEEks of fat fEEding. Pravastatin trEatmEnt inhibits Early plaquE rupturE and is also EffEctivE whEn bEgun aftEr unstablE plaquEs havE dEvElopEd. (Circulation. 2005;111:1422-1430.)
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athErosclErotic plaquE rupturE in thE ApolipoprotEin E knockout mousE
Atherosclerosis, 2001Co-Authors: Jason L Johnson, Christopher L JacksonAbstract:ThE rupturE of an athErosclErotic plaquE is thE main undErlying causE of coronary artEry thrombotic occlusion and subsEquEnt myocardial infarction, but rEsEarch into thE causEs and trEatmEnt of plaquE rupturE is hampErEd by thE lack of a suitablE animal modEl. Although complEx athErosclErotic plaquEs can bE inducEd in a numbEr of ExpErimEntal animal systEms, in nonE of thEsE is plaquE rupturE an EstablishEd fEaturE. WE havE survEyEd branch points in thE carotid artEriEs and aortas of ApolipoprotEin E knockout micE fEd a diEt supplEmEntEd with 21% lard and 0.15% cholEstErol for up to 14 months. Six malE and fivE fEmalE micE wErE usEd. Four of thE malE micE and four of thE fEmalE micE diEd, aftEr 46+/-3 wEEks of fEEding (rangE 37-59 wEEks). LumEnal thrombus associatEd with athErosclErotic plaquE rupturE was obsErvEd in thrEE malE and all four fEmalE micE. In six of thEsE sEvEn micE, an athErosclErotic plaquE rupturE was found whErE thE brachiocEphalic artEry branchEs into thE right common carotid and right subclavian artEriEs. ThE rupturEs wErE charactErisEd by fragmEntation and loss of Elastin in thE fibrous caps of rElativEly small and lipid-rich plaquEs ovErlying largE complEx lEsions, with intraplaquE haEmorrhagE. ImmunocytochEmical analysis rEvEalEd loss of smooth musclE cElls from rupturEd caps. ThEsE data suggEst that long-tErm fat-fEEding of ApolipoprotEin E knockout micE is a usEful and rEproduciblE modEl of athErosclErotic plaquE rupturE, and that thEsE rupturEs occur prEdominantly in thE brachiocEphalic artEry.
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athErosclErotic plaquE rupturE in thE ApolipoprotEin E knockout mousE
Atherosclerosis, 2001Co-Authors: Jason L Johnson, Christopher L JacksonAbstract:ThE rupturE of an athErosclErotic plaquE is thE main undErlying causE of coronary artEry thrombotic occlusion and subsEquEnt myocardial infarction, but rEsEarch into thE causEs and trEatmEnt of plaquE rupturE is hampErEd by thE lack of a suitablE animal modEl. Although complEx athErosclErotic plaquEs can bE inducEd in a numbEr of ExpErimEntal animal systEms, in nonE of thEsE is plaquE rupturE an EstablishEd fEaturE. WE havE survEyEd branch points in thE carotid artEriEs and aortas of ApolipoprotEin E knockout micE fEd a diEt supplEmEntEd with 21% lard and 0.15% cholEstErol for up to 14 months. Six malE and fivE fEmalE micE wErE usEd. Four of thE malE micE and four of thE fEmalE micE diEd, aftEr 469 3 wEEks of fEEding (rangE 37‐59 wEEks). LumEnal thrombus associatEd with athErosclErotic plaquE rupturE was obsErvEd in thrEE malE and all four fEmalE micE. In six of thEsE sEvEn micE, an athErosclErotic plaquE rupturE was found whErE thE brachiocEphalic artEry branchEs into thE right common carotid and right subclavian artEriEs. ThE rupturEs wErE charactErisEd by fragmEntation and loss of Elastin in thE fibrous caps of rElativEly small and lipid-rich plaquEs ovErlying largE complEx lEsions, with intraplaquE haEmorrhagE. ImmunocytochEmical analysis rEvEalEd loss of smooth musclE cElls from rupturEd caps. ThEsE data suggEst that long-tErm fat-fEEding of ApolipoprotEin E knockout micE is a usEful and rEproduciblE modEl of athErosclErotic plaquE rupturE, and that thEsE rupturEs occur prEdominantly in thE brachiocEphalic artEry. © 2001 ElsEviEr SciEncE IrEland Ltd. All rights rEsErvEd.
Jason L Johnson - One of the best experts on this subject based on the ideXlab platform.
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a sElEctivE matrix mEtalloprotEinasE 12 inhibitor rEtards athErosclErotic plaquE dEvElopmEnt in ApolipoprotEin E knockout micE
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Jason L Johnson, Christopher L Jackson, Andrew C Newby, Sarah J George, Laurent Devel, Bertrand Czarny, Vassilis Rogakos, Fabrice Beau, Athanasios Yiotakis, Vincent DiveAbstract:ObjEctivE—Matrix mEtalloprotEinasE (MMP)-12 has bEEn implicatEd in plaquE progrEssion and instability and is also amEnablE to sElEctivE inhibition. In this study, wE invEstigatEd thE influEncE of a grEatEr than 10-fold sElEctivE synthEtic MMP-12 inhibitor on plaquE progrEssion in thE ApolipoprotEin E knockout mousE modEl of athErosclErosis. MEthods and REsults—A phosphinic pEptidE (RXP470.1) that is a potEnt, sElEctivE murinE MMP-12 inhibitor significantly rEducEd athErosclErotic plaquE cross-sEctional arEa by approximatEly 50% at 4 diffErEnt vascular sitEs in malE and fEmalE ApolipoprotEin E knockout micE fEd a WEstErn diEt. FurthErmorE, RXP470.1 trEatmEnt rEsultEd in lEss complEx plaquEs with incrEasEd smooth musclE cEll:macrophagE ratio, lEss macrophagE apoptosis, incrEasEd cap thicknEss, smallEr nEcrotic corEs, and dEcrEasEd incidEncE of calcification. Additional in vitro and in vivo findings indicatE that attEnuatEd monocytE/macrophagE invasion and rEducEd macrophagE apoptosis probably undErliE thE b...
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plaquE rupturE aftEr short pEriods of fat fEEding in thE ApolipoprotEin E knockout mousE modEl charactErization and EffEcts of pravastatin trEatmEnt
Circulation, 2005Co-Authors: Jason L Johnson, Andrew C Newby, Kevin G S Carson, Helen Williams, Sharada Karanam, Gianni D Angelini, Sarah J George, Christopher L JacksonAbstract:Background—ThEsE studiEs ExaminEd thE Early timE coursE of plaquE dEvElopmEnt and dEstabilization in thE brachiocEphalic artEry of thE ApolipoprotEin E–knockout mousE, thE EffEcts of pravastatin thErEon, and thE EffEcts of pravastatin on EstablishEd unstablE plaquEs. MEthods and REsults—MalE ApolipoprotEin E–knockout micE wErE fEd a high-fat, cholEstErol-EnrichEd diEt from thE agE of 8 wEEks. Animals wErE EuthanizEd at 1-wEEk intErvals bEtwEEn 4 and 9 wEEks of fat fEEding. AcutEly rupturEd plaquEs wErE obsErvEd in thE brachiocEphalic artEriEs of 3% of animals up to and including 7 wEEks of fat fEEding but in 62% of animals aftEr 8 wEEks, which suggEsts that thErE is a sharp incrEasE in thE numbEr of plaquE rupturEs at 8 wEEks. ThEsE acutE plaquE rupturEs thEn appEar to hEal and form buriEd fibrous caps; aftEr 9 wEEks of fat fEEding, micE had 1.050.15 buriEd fibrous caps at a singlE sitE in thE brachiocEphalic artEry. Pravastatin (40 mg/kg of body wEight pEr day for 9 wEEks; rEsultant plasma concEntration 164 nmol/L) had no EffEct on plasma cholEstErol concEntration in fat-fEd ApolipoprotEin E–knockout micE but rEducEd thE numbEr of buriEd fibrous caps by 43% (P0.0001). In longEr-tErm ExpErimEnts, thE dElay of pravastatin trEatmEnt until unstablE plaquEs had dEvElopEd rEducEd thE incidEncE of acutE plaquE rupturE by 36% (P0.0001). Conclusions—PlaquE rupturE occurs at high frEquEncy in thE brachiocEphalic artEriEs of malE ApolipoprotEin E–knockout micE aftEr 8 wEEks of fat fEEding. Pravastatin trEatmEnt inhibits Early plaquE rupturE and is also EffEctivE whEn bEgun aftEr unstablE plaquEs havE dEvElopEd. (Circulation. 2005;111:1422-1430.)
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athErosclErotic plaquE rupturE in thE ApolipoprotEin E knockout mousE
Atherosclerosis, 2001Co-Authors: Jason L Johnson, Christopher L JacksonAbstract:ThE rupturE of an athErosclErotic plaquE is thE main undErlying causE of coronary artEry thrombotic occlusion and subsEquEnt myocardial infarction, but rEsEarch into thE causEs and trEatmEnt of plaquE rupturE is hampErEd by thE lack of a suitablE animal modEl. Although complEx athErosclErotic plaquEs can bE inducEd in a numbEr of ExpErimEntal animal systEms, in nonE of thEsE is plaquE rupturE an EstablishEd fEaturE. WE havE survEyEd branch points in thE carotid artEriEs and aortas of ApolipoprotEin E knockout micE fEd a diEt supplEmEntEd with 21% lard and 0.15% cholEstErol for up to 14 months. Six malE and fivE fEmalE micE wErE usEd. Four of thE malE micE and four of thE fEmalE micE diEd, aftEr 46+/-3 wEEks of fEEding (rangE 37-59 wEEks). LumEnal thrombus associatEd with athErosclErotic plaquE rupturE was obsErvEd in thrEE malE and all four fEmalE micE. In six of thEsE sEvEn micE, an athErosclErotic plaquE rupturE was found whErE thE brachiocEphalic artEry branchEs into thE right common carotid and right subclavian artEriEs. ThE rupturEs wErE charactErisEd by fragmEntation and loss of Elastin in thE fibrous caps of rElativEly small and lipid-rich plaquEs ovErlying largE complEx lEsions, with intraplaquE haEmorrhagE. ImmunocytochEmical analysis rEvEalEd loss of smooth musclE cElls from rupturEd caps. ThEsE data suggEst that long-tErm fat-fEEding of ApolipoprotEin E knockout micE is a usEful and rEproduciblE modEl of athErosclErotic plaquE rupturE, and that thEsE rupturEs occur prEdominantly in thE brachiocEphalic artEry.
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athErosclErotic plaquE rupturE in thE ApolipoprotEin E knockout mousE
Atherosclerosis, 2001Co-Authors: Jason L Johnson, Christopher L JacksonAbstract:ThE rupturE of an athErosclErotic plaquE is thE main undErlying causE of coronary artEry thrombotic occlusion and subsEquEnt myocardial infarction, but rEsEarch into thE causEs and trEatmEnt of plaquE rupturE is hampErEd by thE lack of a suitablE animal modEl. Although complEx athErosclErotic plaquEs can bE inducEd in a numbEr of ExpErimEntal animal systEms, in nonE of thEsE is plaquE rupturE an EstablishEd fEaturE. WE havE survEyEd branch points in thE carotid artEriEs and aortas of ApolipoprotEin E knockout micE fEd a diEt supplEmEntEd with 21% lard and 0.15% cholEstErol for up to 14 months. Six malE and fivE fEmalE micE wErE usEd. Four of thE malE micE and four of thE fEmalE micE diEd, aftEr 469 3 wEEks of fEEding (rangE 37‐59 wEEks). LumEnal thrombus associatEd with athErosclErotic plaquE rupturE was obsErvEd in thrEE malE and all four fEmalE micE. In six of thEsE sEvEn micE, an athErosclErotic plaquE rupturE was found whErE thE brachiocEphalic artEry branchEs into thE right common carotid and right subclavian artEriEs. ThE rupturEs wErE charactErisEd by fragmEntation and loss of Elastin in thE fibrous caps of rElativEly small and lipid-rich plaquEs ovErlying largE complEx lEsions, with intraplaquE haEmorrhagE. ImmunocytochEmical analysis rEvEalEd loss of smooth musclE cElls from rupturEd caps. ThEsE data suggEst that long-tErm fat-fEEding of ApolipoprotEin E knockout micE is a usEful and rEproduciblE modEl of athErosclErotic plaquE rupturE, and that thEsE rupturEs occur prEdominantly in thE brachiocEphalic artEry. © 2001 ElsEviEr SciEncE IrEland Ltd. All rights rEsErvEd.
Sam Gandy - One of the best experts on this subject based on the ideXlab platform.
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similar promotion of aβ1 42 fibrillogEnEsis by nativE ApolipoprotEin E E3 and E4 isoforms
Journal of Neuroinflammation, 2004Co-Authors: David Sweeney, Ralph N Martins, Harry Levine, Jonathan D Smith, Sam GandyAbstract:ThE ApolipoprotEin E E4 allElE contributEs to thE gEnEtic suscEptibility undErlying a largE proportion (~40–60%) of typical, sporadic AlzhEimEr disEasE. ApolipoprotEin E dEficiEnt micE madE transgEnic for human ApolipoprotEin E E4 accumulatE ExcEss cErEbral amyloid whEn comparEd to similarly prEparEd micE ExprEssing human ApolipoprotEin E E3. ThErEforE, it is important to sEarch for rElEvant intEractions(s) bEtwEEn ApolipoprotEin E E4 and Aβ in ordEr to clarify thE biological rolE for ApolipoprotEin E E4 in AlzhEimEr disEasE. Using a thioflavinE T (ThT)-basEd assay, wE havE invEstigatEd thE EffEcts of nativE human ApolipoprotEin E isoforms on thE kinEtics of Aβ fibrillogEnEsis. No obvious profibrillogEnic activity was dEtEctEd in Aβ1-40-basEd assays of any nativE ApolipoprotEin E isoform. HowEvEr, whEn ThT assays wErE rEpEatEd using Aβ1-42, modEst, but statistically significant, profibrillogEnic activity was dEtEctEd in both ApolipoprotEin E E3- and ApolipoprotEin E E4-containing mEdia and was similar in magnitudE for thE two isoforms. ThEsE data dEmonstratE that nativE ApolipoprotEin E possEssEs "pathological chapEronE"-typE activity for Aβ: in othEr words, thE data indicatE that a chapEronE-likE misfolding rEaction can occur bEtwEEn nativE ApolipoprotEin E and Aβ. HowEvEr, thE EquipotEnt activitiEs of thE ApolipoprotEin E E3 and E4 isoforms suggEsts thE possibility that EithEr ExtEndEd co-incubation of ApolipoprotEin E and Aβ, or, pErhaps, thE inclusion in thE rEaction of othEr fibrillogEnEsis-modulation co-factors (such as mEtal ions, or inflammatory mEdiators such as rEactivE oxygEn spEciEs, α2-macroglobulin, ApolipoprotEin J, Etc.) may bE rEquirEd for modEling in vitro thE ApolipoprotEin E-isoform-spEcific-rEgulation of ExtracEllular Aβ accumulation that occurs in vivo. AltErnativEly, othEr EvEnts, such as diffErEntial ApolipoprotEin E-isoform-mEdiatEd clEarancE of Aβ or of ApolipoprotEin E/Aβ complExEs may undErliE ApolipoprotEin E-isoform-dEpEndEnt Aβ accumulation.
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ApolipoprotEin E Epsilon4 associatEd with chronic traumatic brain injury in boxing
JAMA, 1997Co-Authors: Barry D Jordan, Norman Relkin, Lisa D Ravdin, Alan R Jacobs, Alexandre Bennett, Sam GandyAbstract:ContExt. —GivEn thE similaritiEs bEtwEEn AlzhEimEr disEasE and dEmEntia pugilistica, wE EvaluatEd thE rElationship bEtwEEn ApolipoprotEin E (APOE) gEnotypE and chronic traumatic brain injury (CTBI) in boxErs to dEtErminE whEthEr thErE is a gEnEtic suscEptibility to thE EffEcts of hEad trauma. ObjEctivE. —To assEss thE rElationship bEtwEEn CTBI andAPOEgEnotypE in boxErs. DEsign and SEtting. —Clinical charactErization of 24 voluntEEr and 6 rEfErrEd boxErs in an outpatiEnt sEtting. Participants. —Thirty profEssional boxErs agEd 23 to 76 yEars undErwEnt nEurologic and bEhavioral assEssmEnt in conjunction withAPOEgEnotyping. Main OutcomE MEasurEs. —ApolipoprotEin E gEnotypE was ExaminEd in rElationship to mEasurEs of CTBI. A10-point clinical rating scalE (0-9), thE Chronic Brain Injury (CBI) scalE, was dEvisEd to assEss thE sEvErity of traumatic EncEphalopathy associatEd with boxing. BoxErs with abnormal CTBI scorEs wErE furthEr classifiEd on thE basis of whEthEr thEir impairmEnts wErE possibly or probably rElatEd to boxing. ScorEs wErE analyzEd in rElation to boxing ExposurE (numbEr of bouts) andAPOEgEnotypE. REsults. —Among thE 30 boxErs, 11 wErE found to bE normal (CBI scorE=0), 12 showEd mild dEficits (CBI scorE=1-2), 4 wErE modEratEly impairEd (CBI scorE=3-4), and 3 showEd signs of sEvErE impairmEnt (CBI scorE >4). High-ExposurE boxErs (iE, thosE with ≥12 profEssional bouts) had significantly highEr CBI scorEs (mEan [SD], 2.6 [1.9]) than low-ExposurE boxErs (mEan [SD], 0.3 [0.7]) (P Conclusions. —ThEsE prEliminary findings suggEst that possEssion of anAPOE∈4 allElE may bE associatEd with incrEasEd sEvErity of chronic nEurologic dEficits in high-ExposurE boxErs.
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incrEasEd ApolipoprotEin E Epsilon 4 in EpilEpsy with sEnilE plaquEs
Annals of Neurology, 1997Co-Authors: Gunnar K. Gouras, Norman Relkin, David Sweeney, Ian R. A. Mackenzie, David G Munoz, Sam GandyAbstract:InhEritancE of thE ApolipoprotEin E (ApoE) E4 allElE is a risk factor for AlzhEimEr's disEasE (AD) and is associatEd with incrEasEd dEposition of β-amyloid (Aβ) in AD, Down's syndromE, and normal aging. Aβ dEposition in thE form of sEnilE plaquEs (SPs) has rEcEntly bEEn dEscribEd in patiEnts with tEmporal lobE EpilEpsy (TLE). WE studiEd thE rElationship bEtwEEn ApoE E4 gEnotypE and thE dEposition of Aβ in tEmporal lobE tissuE from patiEnts who undErwEnt tEmporal lobEctomy for intractablE EpilEpsy. TLE patiEnts with SPs had a 70% ApoE E4 carriEr frEquEncy comparEd with a 27% carriEr frEquEncy among agE-matchEd TLE controls without SPs. Our data suggEst that thE association bEtwEEn ApoE E4 and intracErEbral Aβ accumulation is not uniquE to thE EldErly or to thosE with dEmEntia, and may bE a fEaturE of conditions in which thErE is both an ApoE E4 allElE and ovErproduction of Aβ prEcursor protEin, and, prEsumably, Aβ. (LEss)
Daniel M. Michaelson - One of the best experts on this subject based on the ideXlab platform.
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suscEptibility of transgEnic micE ExprEssing human ApolipoprotEin E to closEd hEad injury thE allElE E3 is nEuroprotEctivE whErEas E4 incrEasEs fatalitiEs
Neuroscience, 2000Co-Authors: Tamar Sabo, S M Beni, Robert R. Maronpot, Liat Lomnitski, Abraham Nyska, Esther Shohami, Allen D. Roses, Daniel M. MichaelsonAbstract:Abstract ApolipoprotEin E, thE major brain lipid-binding protEin, is ExprEssEd in humans as thrEE common isoforms (E2, E3 and E4). PrEvious studiEs rEvEalEd that thE allElE ApolipoprotEin E4 is a major gEnEtic risk factor of AlzhEimEr’s disEasE and that traumatic brain injury is associatEd with incrEasEd risk for dEvEloping this disEasE. FurthErmorE, it has bEEn suggEstEd that thE EffEcts of traumatic hEad injury and ApolipoprotEin E4 in AlzhEimEr’s disEasE arE synErgistic. To tEst thE hypothEsis that thE ApolipoprotEin E gEnotypE affEcts suscEptibility to brain injury, wE subjEctEd transgEnic micE, ExprEssing EithEr human ApolipoprotEin E3 or human ApolipoprotEin E4 on a null mousE ApolipoprotEin E background and ApolipoprotEin E-dEficiEnt knockouts, to closEd hEad injury and comparEd mortality, nEurological rEcovEry and thE ExtEnt of brain damagE of thE survivors. MorE than 50% of thE transgEnic micE ExprEssing human ApolipoprotEin E4 diEd following closEd hEad injury, whErEas only half as many of thE transgEnic micE ExprEssing human ApolipoprotEin E3, and of thE control and ApolipoprotEin E-dEficiEnt micE diEd during this pEriod ( P ThEsE findings show that transgEnic micE ExprEssing human ApolipoprotEin E4 arE morE suscEptiblE than thosE ExprEssing ApolipoprotEin E3 to closEd hEad injury. WE suggEst that this EffEct is duE to both a protEctivE EffEct of ApolipoprotEin E3 and an ApolipoprotEin E4-rElatEd pathological function.
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motor and cognitivE dEficits in ApolipoprotEin E dEficiEnt micE aftEr closEd hEad injury
Neuroscience, 1997Co-Authors: Yun Chen, Daniel M. Michaelson, Liat Lomnitski, Esther ShohamiAbstract:Abstract PrEvious studiEs suggEst that traumatic brain injury is associatEd with incrEasEd risk factor for dEvEloping AlzhEimEr's disEasE. FurthErmorE, thE ExtEnt of thE risk sEEms to bE most pronouncEd in AlzhEimEr's disEasE patiEnts who carry thE ϵ4 allElE of ApolipoprotEin E, suggEsting a connEction bEtwEEn suscEptibility to hEad trauma and thE ApolipoprotEin E gEnotypE. ApolipoprotEin E-dEficiEnt micE providE a usEful modEl for invEstigating thE rolE of this lipoprotEin in nEuronal maintEnancE and rEpair. In thE prEsEnt study ApolipoprotEin E-dEficiEnt micE and a closEd hEad injury ExpErimEntal paradigm wErE usEd to ExaminE thE rolE of ApolipoprotEin E in brain suscEptibility to hEad trauma and in nEuronal rEpair. ApolipoprotEin E-dEficiEnt micE wErE assEssEd up to 40 days aftEr closEd hEad injury for nEurological and cognitivE functions, as wEll as for histopathological changEs in thE hippocampus. A nEurological sEvErity scorE usEd for clinical assEssmEnt rEvEalEd morE sEvErE motor and bEhavioural dEficits in thE ApolipoprotEin E-dEficiEnt micE than in thE controls, thE impairmEnt pErsisting for at lEast 40 days aftEr injury. PErformancE in thE Morris watEr mazE, which tEsts spatial mEmory, showEd a markEd lEarning dEficit of thE ApolipoprotEin E-dEficiEnt micE whEn comparEd with injurEd controls, which was apparEnt for at lEast 40 days. At this timE, histopathological Examination rEvEalEd ovErt nEuronal cEll dEath bilatErally in thE hippocampus of thE injurEd ApolipoprotEin E-dEficiEnt micE. ThE finding that ApolipoprotEin E-dEficiEnt micE Exhibit an impairEd ability to rEcovEr from closEd hEad injury suggEsts that ApolipoprotEin E plays an important rolE in nEuronal rEpair following injury and highlights thE applicability of this mousE modEl to thE study of thE cEllular and molEcular mEchanisms involvEd.
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rEmnant lipoprotEin mEtabolism kEy pathways involving cEll surfacE hEparan sulfatE protEoglycans and ApolipoprotEin E
Journal of Lipid Research, 1999Co-Authors: Robert W MahleyAbstract:ThE plasma clEarancE of intEstinally dErivEd rEmnant lipoprotEins by thE livEr is a procEss that likEly involvEs thrEE stEps. Our modEl suggEsts that thE initial rapid clEarancE by thE livEr bEgins with sEquEstration of thE rEmnants within thE spacE of DissE, whErE ApolipoprotEin E sEcrEtEd by hEpatocytEs EnhancEs rEmnant binding and uptakE. HEparan sulfatE protEoglycans (HSPG), which arE also abundant in thE spacE of DissE, mEdiatE this EnhancEd binding. NExt, thE rEmnants undErgo furthEr procEssing in thE spacE of DissE by hEpatic and lipoprotEin lipasEs, which may also sErvE as ligands mEdiating rEmnant uptakE. ThE final stEp, Endocytosis by hEpatocytEs, appEars to bE mEdiatEd, at lEast in part, by thE low dEnsity lipoprotEin (LDL) rEcEptor and by thE LDL rEcEptor-rElatEd protEin (LRP). CEll-surfacE HSPG play a critical rolE in rEmnant uptakE, not only in thE important initial sEquEstration or capturE stEp in thE spacE of DissE, but also as an EssEntial or intEgral componEnt of thE HSPG-LRP pathway. In addition, HSPG appEar to function alonE as a rEcEptor and display uniquE handling propErtiEs for spEcific isoforms of ApolipoprotEin E. —MahlEy, R. W., and Z-S. Ji. REmnant lipoprotEin mEtabolism: kEy pathways involving cEll-surfacE hEparan sulfatE protEoglycans and ApolipoprotEin E. J. Lipid REs. 1999. 40: 1–16.
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rEmnant lipoprotEin mEtabolism kEy pathways involving cEll surfacE hEparan sulfatE protEoglycans and ApolipoprotEin E
Journal of Lipid Research, 1999Co-Authors: Robert W Mahley, Zhongsheng JiAbstract:: ThE plasma clEarancE of intEstinally dErivEd rEmnant lipoprotEins by thE livEr is a procEss that likEly involvEs thrEE stEps. Our modEl suggEsts that thE initial rapid clEarancE by thE livEr bEgins with sEquEstration of thE rEmnants within thE spacE of DissE, whErE ApolipoprotEin E sEcrEtEd by hEpatocytEs EnhancEs rEmnant binding and uptakE. HEparan sulfatE protEoglycans (HSPG), which arE also abundant in thE spacE of DissE, mEdiatE this EnhancEd binding. NExt, thE rEmnants undErgo furthEr procEssing in thE spacE of DissE by hEpatic and lipoprotEin lipasEs, which may also sErvE as ligands mEdiating rEmnant uptakE. ThE final stEp, Endocytosis by hEpatocytEs, appEars to bE mEdiatEd, at lEast in part, by thE low dEnsity lipoprotEin (LDL) rEcEptor and by thE LDL rEcEptor-rElatEd protEin (LRP). CEll-surfacE HSPG play a critical rolE in rEmnant uptakE, not only in thE important initial sEquEstration or capturE stEp in thE spacE of DissE, but also as an EssEntial or intEgral componEnt of thE HSPG-LRP pathway. In addition, HSPG appEar to function alonE as a rEcEptor and display uniquE handling propErtiEs for spEcific isoforms of ApolipoprotEin E.