morris-water-maze-test-optimization-for-mouse-strain-testing

Morris Water Maze Test: Optimization for Mouse Strain and Testing Environment

 The Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in transgenic mouse models of disease, ...

N. Bud Grossman Center for Memory Research and Care, University of Minnesota

GRECC, VA Medical Center

Hippocampal synaptic plasticity was studied in transgenic mice over-expressing human alpha-synuclein containing the A30P Parkinson's disease mutation. Medial perforant path-dentate granule cell synapses showed enhanced paired-pulse depression (PPD) for short interpulse intervals (< 200 ms), without differences in basal transmission. Extracellular calcium reduction failed to rescue the enhanced PPD. Paired-pulse facilitation in the CA1 region was normal in slices from transgenic mice, but enhanced synaptic depression was revealed upon repetitive stimulation of the Schaffer collaterals. Long-term potentiation in the CA1 field was not impaired in slices from transgenic mice. These results suggest that mutant alpha-synuclein accumulation impairs short-term changes in synaptic strength when neurotransmitter availability is limited due to enhanced release probability or repetitive synaptic activity.

Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein transgenic mice.

To investigate lipid rafts as a site where amyloid beta protein (Abeta) oligomers might accumulate and cause toxicity in Alzheimer's disease (AD), we analyzed Abeta in the Tg2576 transgenic mouse model of AD. Abeta was highly concentrated in lipid rafts, which comprise a small fraction of brain volume but contain 27% of brain Abeta42 and 24% of Abeta40 in young mice. In the Tg2576 model, memory impairment begins at 6 months before amyloid plaques are visible. Here we show that Abeta dimers appear in lipid rafts at 6 months and that raft Abeta, which is primarily dimeric, rapidly accumulates reaching levels >500x those in young mice by 24-28 months. A similar large accumulation of dimeric Abeta was observed in lipid rafts from AD brain. In contrast to extracellular amyloid fibrils, which are SDS-insoluble, virtually all Abeta in lipid rafts is SDS soluble. Coupled with recent studies showing that synthetic and naturally occurring Abeta oligomers can inhibit hippocampal long-term potentiation, the in vivo age-dependent accumulation of SDS-soluble Abeta dimers in lipid rafts at the time when memory impairment begins in Tg2576 mice provides strong evidence linking Abeta oligomers to memory impairment. After dimeric Abeta began to accumulate in lipid rafts of the Tg2576 brain, apolipoprotein E (ApoE) and then phosphorylated tau accumulated. A similar increase in ApoE and a large increase in phosphorylated tau was observed in lipid rafts from AD brain. These findings suggest that lipid rafts may be an important site for interaction between dimeric Abeta, ApoE, and tau.

Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease.

Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Abeta expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB/NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Abeta peptide in plasma. However, analysis of plasma Abeta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Abeta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Abeta.

Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression.

In search of the molecular basis of memory loss in Alzheimer disease.

&#x670A;&#x75C5;&#x6BD2;&#x75BE;&#x75C5;&#x88AB;&#x9020;&#x6210;&#x7684;&#x8F6C;&#x6362;&#x901A;&#x5E38;&#x6298;&#x53E0;&#x3001; &#x975E;&#x81F4;&#x75C5;&#x6027;&#x9F3B;&#x606F;&#x8089;&#x670A;&#x86CB;&#x767D; (PrP(C)) &#x5230;&#x7EA0;&#x7F20;&#x3001; &#x81F4;&#x75C5;&#x6027;&#x5F02;&#x6784;&#x4F53; &#xFF08;PrP(Sc))&#x3002;&#x670A;&#x75C5;&#x6BD2;&#x63A5;&#x79CD;&#x5B9E;&#x9A8C;&#x5C0F;&#x9F20;&#x540C;&#x6E90; PrP(C) &#x5206;&#x5B50;&#x8868;&#x793A;&#x5BF9;&#x4E0D;&#x540C;&#x9057;&#x4F20;&#x80CC;&#x666F;&#x663E;&#x793A;&#x4E0D;&#x540C;&#x65F6;&#x95F4;&#x3001; &#x6307;&#x793A;&#x8F6C;&#x6362;&#x53CD;&#x5E94;&#x53EF;&#x80FD;&#x53D7;&#x5230;&#x5176;&#x4ED6;&#x57FA;&#x56E0;&#x4EA7;&#x54C1;&#x7684;&#x5B75;&#x5316;&#x3002;&#x82E5;&#x8981;&#x6807;&#x8BC6;&#x6709;&#x52A9;&#x4E8E;&#x670A;&#x75C5;&#x6BD2;&#x81F4;&#x75C5;&#x673A;&#x7406;&#x7684;&#x57FA;&#x56E0;&#xFF0C;&#x6211;&#x4EEC;&#x5206;&#x6790;&#x4E86;&#x670A;&#x75C5;&#x6BD2;&#x5C0F;&#x9F20;&#x57FA;&#x56E0;&#x4EA7;&#x7269;&#x662F;&#x706D;&#x6D3B;&#x3001; &#x6DD8;&#x6C70;&#x6216;&#x5916;&#x57DF;&#x7684;&#x5B75;&#x5316;&#x65F6;&#x95F4;&#x3002;&#x6211;&#x4EEC;&#x6D4B;&#x8BD5; 20 &#x4E2A;&#x5019;&#x9009;&#x57FA;&#x56E0;&#xFF0C;&#x56E0;&#x4E3A;&#x8981;&#x4E48; colocalize &#x4E0E;&#x8986;&#x68C0;&#x59D4;&#x5458;&#x4F1A;&#xFF0C;&#x5176;&#x4EA7;&#x54C1;&#x4E0E;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x7684;&#x5173;&#x8054;&#x3001; &#x9AD8;&#x67B6;&#x5728;&#x670A;&#x75C5;&#x6BD2;&#x75BE;&#x75C5;&#x6216;&#x529F;&#x80FD;&#xFF0C;PrP &#x4ECB;&#x5BFC;&#x4FE1;&#x53F7;&#x3001; PrP &#x7CD6;&#x57FA;&#x5316;&#x6216;&#x86CB;&#x767D;&#x4FDD;&#x517B;&#x3002;&#x800C;&#x4E00;&#x4E9B;&#x6D4B;&#x8BD5;&#x7684;&#x8003;&#x751F;&#x53EF;&#x80FD;&#x5728; PrP(C) &#x7684;&#x6B63;&#x5E38;&#x529F;&#x80FD;&#x65B9;&#x9762;&#x53D1;&#x6325;&#x4F5C;&#x7528;&#xFF0C;&#x6211;&#x4EEC;&#x7684;&#x6570;&#x636E;&#x663E;&#x793A;&#x4EE5;&#x524D;&#x670A;&#x75C5;&#x6BD2;&#x590D;&#x5236;&#x8FC7;&#x7A0B;&#x4E2D;&#x7275;&#x6D89;&#x5230;&#x8BB8;&#x591A;&#x57FA;&#x56E0;&#x6709;&#x670A;&#x75C5;&#x6BD2;&#x75C5;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x4E0A;&#x6CA1;&#x6709;&#x660E;&#x663E;&#x7684;&#x6548;&#x679C;&#x3002;&#x867D;&#x7136;&#x5927;&#x591A;&#x6570;&#x57FA;&#x56E0;&#x6D4B;&#x8BD5;&#x5F71;&#x54CD;&#x4E0D;&#x5927;&#x7684;&#x5B58;&#x6D3B;&#x65F6;&#x95F4;&#xFF0C;&#x6D88;&#x878D; &#xFF08;A4&#xFF09; &#x6DC0;&#x7C89;&#x6837;&#x524D;&#x4F53;&#x86CB;&#x767D; (App) &#x6216;&#x767D;&#x7EC6;&#x80DE;&#x4ECB;&#x7D20;-1 &#x53D7;&#x4F53;&#xFF0C;&#x6211; &#xFF08;Il1r1&#xFF09;&#xFF0C;&#x5206;&#x522B;&#x952E;&#x5165;&#x548C;&#x8F6C;&#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x7684;&#x4EBA;&#x7C7B;&#x7684;&#x8D85;&#x6C27;&#x5316;&#x7269;&#x6B67;&#x5316;&#x9176; 1 (SOD1) &#x5EF6;&#x957F;&#x5B75;&#x80B2;&#x65F6;&#x95F4; 13&#x3001; 16%&#x548C; 19%&#x3002;

&#x670A;&#x75C5;&#x6BD2;&#x81F4;&#x75C5;&#x673A;&#x7406;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#x7684;&#x57FA;&#x56E0;&#x3002;

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

Genes contributing to prion pathogenesis.

Les maladies &agrave; prions sont caus&eacute;es par la conversion d&#39;une isoforme normalement pli&eacute;e, non pathog&egrave;ne de la prot&eacute;ine de prion (PrP(C)) d&#39;une isoforme mal repli&eacute;e, pathog&egrave;ne (PrP(Sc)). Exp&eacute;riences d&#39;inoculation de prion chez les souris exprimant des mol&eacute;cules homologues PrP(C) sur diff&eacute;rents fonds g&eacute;n&eacute;tiques affichent diff&eacute;rente d&#39;incubation times, indiquant que la r&eacute;action de conversion peut &ecirc;tre influenc&eacute;e par d&#39;autres produits de g&egrave;ne. Pour identifier les g&egrave;nes qui contribuent &agrave; la pathog&eacute;n&egrave;se du prion, nous avons analys&eacute; les temps d&#39;incubation des prions chez les souris dont le produit du g&egrave;ne a &eacute;t&eacute; inactiv&eacute;, assomm&eacute; ou surexprim&eacute;. Nous avons test&eacute; 20 g&egrave;nes candidats, parce que leurs produits soit sont colocalis&eacute;es avec PrP, sont associ&eacute;es &agrave; la maladie d&#39;Alzheimer, sont &eacute;lev&eacute;s au cours de la maladie &agrave; prion ou fonctionner en PrP-mediated signalisation, glycosylation PrP ou l&#39;entretien de la prot&eacute;ine. Alors que certains candidats test&eacute;s peuvent avoir un r&ocirc;le dans le fonctionnement normal de PrP(C), nos r&eacute;sultats montrent que plusieurs g&egrave;nes pr&eacute;c&eacute;demment impliqu&eacute;s dans la r&eacute;plication de prion n&#39;ont aucun effet perceptible sur la pathogen&egrave;se des maladies &agrave; prion. Alors que la plupart des g&egrave;nes test&eacute;s n&#39;affectaient pas significativement la dur&eacute;e de survie, l&#39;ablation de la prot&eacute;ine pr&eacute;curseur de la b&ecirc;ta-amylo&iuml;de (A4) (App) ou le r&eacute;cepteur de l&#39;interleukine-1, type I (Il1r1) et temps d&#39;incubation transg&eacute;niques surexprimant humaine superoxyde dismutase 1 (SOD1) prolong&eacute; par les 13, 16 et 19 %, respectivement.

G&egrave;nes contribuant &agrave; la pathogen&egrave;se de prion.

Prion-Krankheiten entstehen durch Umwandlung von einem normalerweise gefaltet, nicht-pathogenen Isoform des Prionproteins (PrP(C)) zu einem misfolded, pathogenen Isoform (PrP(Sc)). Prion Inokulation Experimente an M&auml;usen, die Ausdr&uuml;cken homologe PrP(C) Molek&uuml;le auf verschiedenen genetischen Hintergr&uuml;nden angezeigt verschiedenen Inkubation Zeiten, darauf hinweist, dass die Konvertierung-Reaktion durch andere Genprodukte beeinflusst werden kann. Um Gene zu identifizieren, die zu Prion-Pathogenese beitragen, analysierten wir Inkubationszeiten von Prionen in den M&auml;usen, in denen das Genprodukt wurde inaktiviert, bewusstlos oder Pleuramesotheliom. Wir testeten 20 Kandidatengene, da ihre Produkte, die entweder mit PrP, colocalize Alzheimer-Krankheit zugeordnet sind, sind w&auml;hrend der Prion-Krankheit erh&ouml;ht oder in der PrP-vermittelte Signalisierung, PrP Glycosylation oder Protein Wartung funktionieren. W&auml;hrend einige der Kandidaten getestet eine Rolle in der normalen Funktion des PrP(C) haben, zeigen unsere Daten, dass viele Gene, die zuvor im Prion-Replikation impliziert keine erkennbaren Auswirkungen auf die Pathogenese der Prion-Krankheit. W&auml;hrend die meisten Gene getestet &Uuml;berlebenszeiten signifikant nicht ausgewirkt hat, Ablation des Amyloid Beta (A4)-Vorl&auml;ufer-Protein (App) oder Interleukin-1-Rezeptor Typ I (Il1r1), und transgenen &Uuml;berexpression des menschlichen Superoxiddismutase 1 (SOD1) l&auml;ngere Inkubationszeiten von 13, 16 und 19 %, beziehungsweise.

Gene zu Prion-Pathogenese beitragen.

Malattie da prioni sono causate dalla conversione di un&#39;isoforma normalmente ripiegato, non patogeno della proteina prionica (PrP(C)) di un&#39;isoforma malpiegata, patogeno (PrP(Sc)). Gli esperimenti di inoculazione da prioni nei topi che esprimono molecole PrP(C) omologhe su diversi background genetico visualizzato incubazione diverse volte, che indica che la reazione di conversione pu&ograve; essere influenzata da altri prodotti del gene. Per identificare i geni che contribuiscono alla patogenesi del prione, abbiamo analizzato i tempi di incubazione dei prioni nei topi in cui il prodotto del gene &egrave; stato inattivato, Knock-out o overexpressed. Abbiamo testato 20 geni candidati, perch&eacute; i loro prodotti o colocalize con PrP, sono associati con la malattia di Alzheimer, sono elevati durante la malattia da prioni o funzione PrP-mediata segnalazione, PrP glicosilazione o manutenzione della proteina. Considerando che alcuni dei candidati testati pu&ograve; avere un ruolo nella funzione normale di PrP(C), i nostri dati mostrano che molti geni precedentemente implicati nella replicazione prionica non hanno alcun effetto visibile sulla patogenesi delle malattie da prioni. Mentre la maggior parte dei geni testati non influenzano in modo significativo i tempi di sopravvivenza, l&#39;ablazione della proteina precursore dell&#39;amiloide beta (A4) (App) o recettore dell&#39;interleuchina-1, tipo I (Il1r1) e tempi di incubazione transgenici sovraespressione di umana superossido dismutasi 1 (SOD1) prolungata da 13, 16 e 19%, rispettivamente.

Geni che contribuiscono alla patogenesi del prione.

&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x75C5;&#x306F;&#x901A;&#x5E38; 2 &#x3064;&#x6298;&#x308A;&#x3001;&#x975E;&#x75C5;&#x539F;&#x6027;&#x578B;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x86CB;&#x767D;&#x8CEA; (PrP(C)) &#x306B;&#x8AA4;&#x3063;&#x3066;&#x6298;&#x308A;&#x305F;&#x305F;&#x307E;&#x308C;&#x305F;, &#x75C5;&#x539F;&#x6027;&#x306E;&#x30A2;&#x30A4;&#x30BD; &#x30D5;&#x30A9;&#x30FC;&#x30E0; (PrP(Sc))&#x3002; &#x5909;&#x63DB;&#x306B;&#x3088;&#x3063;&#x3066;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3055;&#x308C;&#x308B;&#x7570;&#x306A;&#x308B;&#x907A;&#x4F1D;&#x80CC;&#x666F;&#x306E;&#x76F8;&#x540C;&#x306B;&#x95A2;&#x3059;&#x308B;&#x8A66;&#x9A13;&#x5206;&#x5B50;&#x3092;&#x767A;&#x73FE;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x63A5;&#x7A2E;&#x5B9F;&#x9A13;&#x56DE;&#x5909;&#x63DB;&#x53CD;&#x5FDC;&#x304C;&#x4ED6;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x88FD;&#x54C1;&#x306B;&#x3088;&#x3063;&#x3066;&#x5F71;&#x97FF;&#x3092;&#x53CA;&#x307C;&#x3055;&#x308C;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3092;&#x793A;&#x3059;&#x5225;&#x306E;&#x30A4;&#x30F3;&#x30AD;&#x30E5;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x8868;&#x793A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x75C5;&#x56E0;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x8B58;&#x5225;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x30A4;&#x30F3;&#x30AD;&#x30E5;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x6642;&#x9593;&#x3067;&#x907A;&#x4F1D;&#x5B50;&#x7523;&#x7269;&#x3060;&#x3063;&#x305F;&#x4E0D;&#x6D3B;&#x5316;&#x3001;&#x30CE;&#x30C3;&#x30AF;&#x30A2;&#x30A6;&#x30C8;&#x307E;&#x305F;&#x306F;&#x3001;&#x904E;&#x5270;&#x767A;&#x73FE;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x306E;&#x5206;&#x6790;&#x3002;&#x3044;&#x305A;&#x308C;&#x304B; PrP &#x3068; colocalize &#x306E;&#x88FD;&#x54C1;&#x306F;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x305F;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x75C5;&#x6642;&#x306B;&#x7BA1;&#x7406;&#x8005;&#x7279;&#x6A29;&#x306F;&#x307E;&#x305F;&#x306F; PrP &#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;, PrP &#x7CD6;&#x9396;&#x4FEE;&#x98FE;&#x3084;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x30E1;&#x30F3;&#x30C6;&#x30CA;&#x30F3;&#x30B9;&#x3067;&#x6A5F;&#x80FD;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005; 20 &#x306E;&#x5019;&#x88DC;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x30C6;&#x30B9;&#x30C8;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30C6;&#x30B9;&#x30C8;&#x5019;&#x88DC;&#x306E;&#x3044;&#x304F;&#x3064;&#x304B;&#x306B;&#x95A2;&#x3059;&#x308B;&#x8A66;&#x9A13;&#x306E;&#x6B63;&#x5E38;&#x306A;&#x6A5F;&#x80FD;&#x306E;&#x5F79;&#x5272;&#x3092;&#x6301;&#x3064;&#x3053;&#x3068;&#x304C;&#x3001;&#x6211;&#x3005; &#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x4EE5;&#x524D;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x8907;&#x88FD;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x591A;&#x304F;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x4E0E;&#x3048;&#x306A;&#x304B;&#x3063;&#x305F;&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x75C5;&#x306E;&#x75C5;&#x614B;&#x304C;&#x3042;&#x308B;&#x306A;&#x3044;&#x3053;&#x3068;&#x3092;&#x898B;&#x308B;&#x3002;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x30C6;&#x30B9;&#x30C8;&#x306F;&#x6709;&#x610F;&#x306B;&#x751F;&#x5B58;&#x671F;&#x9593;&#x306B;&#x5F71;&#x97FF;&#x3057;&#x306A;&#x304B;&#x3063;&#x305F;&#x304C;&#x3001;&#x30A2;&#x30D6;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306E;&#x30A2;&#x30DF;&#x30ED;&#x30A4;&#x30C9; &#x30FB; &#x30D9;&#x30FC;&#x30BF; (A4) &#x524D;&#x99C6;&#x4F53;&#x86CB;&#x767D; &#xFF08;App&#xFF09; &#x307E;&#x305F;&#x306F;&#x30A4;&#x30F3;&#x30BF;&#x30FC;&#x30ED;&#x30A4;&#x30AD;&#x30F3; 1 &#x53D7;&#x5BB9;&#x4F53; I &#x578B; (Il1r1) &#x304A;&#x3088;&#x3073;&#x5EF6;&#x9577;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30B8;&#x30A7;&#x30CB;&#x30C3;&#x30AF;&#x904E;&#x5270;&#x767A;&#x73FE;&#x30D2;&#x30C8; sod 1 (SOD1) &#x306E;&#x30A4;&#x30F3;&#x30AD;&#x30E5;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x6642;&#x9593; 13&#x3001;16&#x3001;19 &#xFF05;&#x3001;&#x305D;&#x308C;&#x305E;&#x308C;&#x3002;

&#x30D7;&#x30EA;&#x30AA;&#x30F3;&#x75C5;&#x56E0;&#x306B;&#x8CA2;&#x732E;&#x907A;&#x4F1D;&#x5B50;&#x3002;

&#xD504;&#xB9AC;&#xC628; &#xB2E8;&#xBC31;&#xC9C8; (PrP(C)) misfolded &#xBCD1;&#xC6D0; &#xC131; isoform (PrP(Sc))&#xC758; &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xC811;&#xD78C;, &#xBE44; &#xBCD1;&#xC6D0; &#xC131; isoform&#xC758; &#xBCC0;&#xD658;&#xC5D0; &#xC758;&#xD574; &#xBC1C;&#xC0DD; &#xD558;&#xB294; &#xD504;&#xB9AC;&#xC628; &#xC9C8;&#xBCD1;. &#xB2E4;&#xB978; &#xC720;&#xC804;&#xC801; &#xBC30;&#xACBD;&#xC5D0; &#xB3D9;&#xC885; PrP(C) &#xBD84;&#xC790;&#xB97C; &#xD45C;&#xD604; &#xD558;&#xB294; &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC811;&#xC885; &#xC2E4;&#xD5D8;&#xC740; &#xD504;&#xB9AC;&#xC628; &#xD45C;&#xC2DC; &#xC2DC;&#xAC04; &#xBCC0;&#xD658; &#xBC18;&#xC751;&#xC744; &#xB2E4;&#xB978; &#xC720;&#xC804;&#xC790; &#xC81C;&#xD488;&#xC5D0; &#xC758;&#xD574; &#xC601;&#xD5A5;&#xC744; &#xBC1B;&#xC744; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xB2E4;&#xB978; &#xBD80; &#xD654;. &#xD504;&#xB9AC;&#xC628; &#xBCD1; &#xC778;&#xC5D0; &#xAE30;&#xC5EC; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790;&#xB97C; &#xC2DD;&#xBCC4; &#xD558;&#xB824;&#xBA74; &#xC6B0;&#xB9AC; prions &#xC0DD;&#xC950;&#xB294; &#xC720;&#xC804;&#xC790; &#xC81C;&#xD488;&#xC740; &#xBE44;&#xD65C;&#xC131;&#xD654;, &#xAE30; &#xC808; &#xD558;&#xAC70;&#xB098; overexpressed&#xC5D0;&#xC11C; &#xBD80; &#xD654; &#xC2DC;&#xAC04; &#xBD84;&#xC11D;. &#xB54C;&#xBB38;&#xC5D0; &#xADF8;&#xB4E4;&#xC758; &#xC81C;&#xD488; &#xC911; PrP&#xC640; colocalize Alzheimer&#xC758; &#xC9C8;&#xBCD1;&#xACFC; &#xAD00;&#xB828; &#xB41C;, &#xD504;&#xB9AC;&#xC628; &#xC9C8;&#xBCD1;, &#xC911; &#xACE0;&#xAC00; &#xB610;&#xB294; &#xC2E0;&#xD638; PrP &#xC911;&#xC7AC;, PrP glycosylation &#xB610;&#xB294; &#xB2E8;&#xBC31;&#xC9C8; &#xC720;&#xC9C0; &#xBCF4;&#xC218; &#xAE30;&#xB2A5; 20 &#xD6C4;&#xBCF4; &#xC720;&#xC804;&#xC790; &#xD14C;&#xC2A4;&#xD2B8;. &#xD14C;&#xC2A4;&#xD2B8; &#xD6C4;&#xBCF4;&#xC758; &#xC77C;&#xBD80; Prp(c)&#xC758; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xAE30;&#xB2A5;&#xC5D0; &#xC5ED;&#xD560;&#xC744; &#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;, &#xBC18;&#xBA74; &#xC6B0;&#xB9AC;&#xC758; &#xB370;&#xC774;&#xD130; &#xD45C;&#xC2DC; &#xC774;&#xC804;&#xC5D0; &#xD504;&#xB9AC;&#xC628; &#xBCF5;&#xC81C;&#xC5D0; &#xC5F0;&#xB8E8; &#xB41C; &#xB9CE;&#xC740; &#xC720;&#xC804;&#xC790;&#xB294; &#xD504;&#xB9AC;&#xC628; &#xC9C8;&#xBCD1;&#xC758; &#xBCD1; &#xC778;&#xC5D0; &#xC544;&#xBB34;&#xB7F0; &#xBCC0;&#xD654;&#xAC00; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB300;&#xBD80;&#xBD84;&#xC758; &#xC720;&#xC804;&#xC790; &#xD14C;&#xC2A4;&#xD2B8;&#xC5D0;&#xC11C;&#xB294; &#xC0DD;&#xC874; &#xC2DC;&#xAC04; &#xD06C;&#xAC8C; &#xBBF8;&#xCE58;&#xC9C0; &#xC54A; &#xC558; &#xC5B4;, &#xD558;&#xB294; &#xB3D9;&#xC548; &#xB179;&#xB9D0; &#xCCB4; &#xBCA0;&#xD0C0; (A4) &#xC804;&#xC870; &#xB2E8;&#xBC31;&#xC9C8; (&#xC751;&#xC6A9; &#xD504;&#xB85C;&#xADF8;&#xB7A8;) &#xB610;&#xB294; interleukin-1 &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC808;&#xC81C; &#xB098; (Il1r1), &#xADF8;&#xB9AC;&#xACE0; 13, 16, 19%&#xB85C; &#xC7A5;&#xAE30; &#xC778;&#xAC04;&#xC758; superoxide dismutase 1 (SOD1)&#xC758; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; overexpression &#xBD80; &#xBC88; &#xAC01;&#xAC01; &#xC785;&#xB825;.

&#xD504;&#xB9AC;&#xC628; &#xBCD1; &#xC778;&#xC5D0; &#xAE30;&#xC5EC; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790;.

Enfermedades pri&oacute;nicas son causadas por la conversi&oacute;n de una isoforma normalmente doblada, no pat&oacute;gena de la prote&iacute;na del pri&oacute;n (PrP(C)) a una isoforma mal plegada, pat&oacute;gena (PrP(Sc)). Experimentos de inoculaci&oacute;n del pri&oacute;n en ratones que expresaban las mol&eacute;culas hom&oacute;logas de PrP(C) en diferentes fondos gen&eacute;ticos muestran incubaci&oacute;n diferente &eacute;pocas, indicando que la reacci&oacute;n de conversi&oacute;n puede ser influenciada por otros productos g&eacute;nicos. Para identificar los genes que contribuyen a la patog&eacute;nesis del pri&oacute;n, se analizaron los tiempos de incubaci&oacute;n de priones en ratones en los que el producto del gene fue inactivado, noqueado o sobreexpresa. Probamos 20 genes candidatos, porque sus productos ya sea colocalize con PrP, est&aacute;n asociados con la enfermedad de Alzheimer, se elevan durante la enfermedad del pri&oacute;n o funci&oacute;n en la se&ntilde;alizaci&oacute;n mediada por PrP, PrP glicosilaci&oacute;n o mantenimiento de la prote&iacute;na. Mientras que algunos de los candidatos probados pueden tener un papel en la funci&oacute;n normal de PrP(C), nuestros datos muestran que muchos genes implicados previamente en la replicaci&oacute;n de priones tienen ning&uacute;n efecto discernible en la patogenia de la enfermedad del pri&oacute;n. Mientras que la mayor&iacute;a de los genes probada no afect&oacute; significativamente los tiempos de supervivencia, ablaci&oacute;n de la prote&iacute;na precursora de amiloide beta (A4) (App) o del receptor de IL-1, tipo I (Il1r1) y tiempos de incubaci&oacute;n de la sobreexpresi&oacute;n transg&eacute;nicos de la humana de la super&oacute;xido dismutasa 1 (SOD1) prolongada por 13, 16 y 19%, respectivamente.

Genes que contribuyen a la patog&eacute;nesis del pri&oacute;n.

To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-beta deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD).

Article	Year
Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein transgenic mice. Neuroreport\| PubMed ID: 12598733	2003
Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 15084661	2004
Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Human molecular genetics\| PubMed ID: 15254013	2004
In search of the molecular basis of memory loss in Alzheimer disease. Alzheimer disease and associated disorders\| PubMed ID: 17132961	2006
Genes contributing to prion pathogenesis. The Journal of general virology\| PubMed ID: 18559949	2008
Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Investigative ophthalmology & visual science\| PubMed ID: 18566467	2008
Neurobiology of disease. Current opinion in neurobiology\| PubMed ID: 22100874	2011

Karen Hsiao Ashe

Biography

JoVE Journal Publications

Other Publications