ApoB100LDLR-- Hypercholesterolaemic Mice as a Model for Mild Cognitive Impairment and Neuronal Damage 英文参考文献.docVIP

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ApoB100LDLR-- Hypercholesterolaemic Mice as a Model for Mild Cognitive Impairment and Neuronal Damage 英文参考文献.doc

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ApoB100LDLR-- Hypercholesterolaemic Mice as a Model for Mild Cognitive Impairment and Neuronal Damage 英文参考文献

ApoB100/LDLR-/-HypercholesterolaemicMiceasa ModelforMildCognitiveImpairmentandNeuronal Damage CarlosRam?′rez,SaletaSierra,InmaculadaTercero,JoseAntonioVa′zquez,AntoniaPineda,Tatiana Manrique,JavierS.Burgos* BioPharmaDivision,NeuronBPh,Granada,Spain Abstract Recentclinicalfindingssupportthenotionthattheprogressivedeteriorationofcholesterolhomeostasisisacentralplayer inAlzheimer’sdisease(AD).Epidemiologicalstudiessuggestthathighmidlifeplasmatotalcholesterollevelsareassociated withanincreasedriskofAD.Thispaperreportstheplasmacholesterolconcentrations,cognitiveperformance,locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL- cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showedcholesterol(totalandfractions)concentrationsconsiderablyhigherthanthoseof18-month-oldwild-typemice.The hypercholesterolaemiaofthetransgenicmicewasassociatedwithaclearlocomotordeficit(asdeterminedbyrotarod,grip strengthandopenfieldtesting)andimpairmentoftheepisodic-likememory(determinedbytheintegratedmemorytest). Thisdeclineinlocomotoractivityandcognitivestatuswasassociatedwithneuriticdystrophyand/orthedisorganizationof theneuronalmicrotubulenetwork,plusanincreaseinastrogliosisandlipidperoxidationinthebrainregionsassociated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atheroscleroticlesionswerepositivelycorrelatedwithage,althoughpotentiatedbythetransgenicgenotype,whilecerebral b-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impair