Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice

InAlzheimerdisease�(AD),�theintracerebralaccumulationofamyloid-β�(Aβ)�peptidesisacriticalyetpoorly� understoodprocess.�Aβ�clearanceviatheblood-brainbarrierisreducedbyapproximately�30%�inADpatients,� buttheunderlyingmechanismsremainelusive.�ABCtransportershavebeenimplicatedintheregulationof� Aβ�levelsinthebrain.�UsingamousemodelofADinwhichtheanimalswerefurthergeneticallymodifiedto� lackspecificABCtransporters,�herewehaveshownthatthetransporterABCC1�hasanimportantroleincere- bralAβ�clearanceandaccumulation.�DeficiencyofABCC1�substantiallyincreasedcerebralAβ�levelswithout� alteringtheexpressionofmostenzymesthatwouldfavortheproductionofAβ�fromtheAβ�precursorprotein.� Incontrast,�activationofABCC1�usingthiethylperazine�(adrugapprovedbytheFDAtorelievenauseaand� vomiting)�markedlyreducedAβ�loadinamousemodelofADexpressingABCC1�butnotinsuchmicelacking� ABCC1.�Thus,�byalteringthetemporalaggregationprofileofAβ,�pharmacologicalactivationofABCtrans- porterscouldimpedetheneurodegenerativecascadethatculminatesinthedementiaofAD.