Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice.docVIP

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Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice.doc

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Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

ApolipoproteinE4CausesAge-andSex-Dependent ImpairmentsofHilarGABAergicInterneuronsand LearningandMemoryDeficitsinMice LauraLeung1,3,YaisaAndrews-Zwilling1,3,SeoYeonYoon1,SachiJain1,5,KarenRing1,5,JessicaDai1, MaxMuWang1,LeslieTong1,5,DavidWalker1,2,YadongHuang1,2,3,4,5 * 1GladstoneInstituteofNeurologicalDisease,SanFrancisco,California,UnitedStatesofAmerica,2GladstoneInstituteofCardiovascularDisease,SanFrancisco,California, United States of America, 3Department of Neurology, University of California San Francisco, San Francisco, California, United States of America, 4Department of Pathology,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica,5BiomedicalSciencesGraduateProgram,UniversityofCaliforniaSan Francisco,SanFrancisco,California,UnitedStatesofAmerica Abstract Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD). ApoE4 has sex-dependent effects, wherebytheriskofdevelopingADishigherinapoE4-expressingfemalesthanmales.However,themechanismunderlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairmentsofhilarGABAergicinterneuronsinfemalemice,leadingtolearningandmemorydeficits.Here,weinvestigate whetherthedetrimentaleffectsofapoE4onhilarGABAergicinterneuronsaresex-dependentusingapoEknock-in(KI)mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbatedbyapoE4.Lossoftheseneuronalpopulationswascorrelatedwiththeseverityofspatiallearningdeficitsat 16monthsofageinfemaleapoE4-KImice;however,thiseffectwasnotobservedinfemaleapoE3-KImice.Incontrast,we foundanincreaseinthenumbersofhilarGABAergicinterneuronswithadvancingageinmaleapoE-KImice,regardlessof apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons