Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease

PROJECT SUMMARYFAST TRACK APPLICATIONAlzheimer s diseaseADis a neurodegenerative disorder affecting overmillion individuals in the United States aloneThe complexity and multifactorial nature of AD pose unique challenges for the development of effective therapiesEfforts to target specific AD related pathways have shown promise in animal studiesonly to fail during human trialsThere is a pressing need to identify novel therapeutic targets and develop new drug candidates for ADCarriers of apolipoproteinapoEone of the three apoE isoformsapoEapoEapoEare associated withof all AD casesmaking apoEthe major genetic risk factor for ADThis proposal builds on four novel findings from our studies of mouse models and human induced pluripotent stem cellhiPSCderived neurons expressing different apoE isoformsFirstexpression of apoEin knock inKImice causes agedependent and cell autonomous impairment of GABAergic interneurons in the hilus of the hippocampuswhich correlates with hippocampal network activity deficits and learning and memory impairmentsSecondoptogenetic inhibition of hilar GABAergic interneuron activity impairs spatial learning and memory in wildtype miceindicating that hilar GABAergic interneuron impairment can directly cause cognitive deficitsThirdtreatment with the GABAA receptor potentiator pentobarbital or transplantation of mouse inhibitory neuron progenitors into the hippocampal hilus rescues the learning and memory deficits in apoEKI miceFourthapoEexpression results in GABAergic interneuron death in hiPSC derived neuronal cultures and in the hippocampal hilus in AD patientsTogetherthese findings strongly suggest that apoEcauses GABAergic interneuron impairmentleading to learning and memory deficitsand represents a novel therapeutic target for ADWe recently identified two classes of small molecules capable of protecting GABAergic neurons from apoEs detrimental effectsThis proposal aims to further developoptimizeand validate compounds targeting apoEinduced GABAergic interneuron impairment as a novel therapeutic approach for ADThe goals of this proposal areto perform ADME and physicochemical studies of the initial compounds and establish a pharmacodynamicPDmarker by in vivo hippocampal electrophysiological recordings in apoEKI miceto identify and optimize the lead small molecule GABAergic interneuron protectors through structure activity relationship studies as well as pharmacokinetic and PD studiesandto test the efficacy of the lead smallmolecule GABAergic interneuron protectors in apoEKI mice and hiPSC derived neurons carrying the apoEallele PROJECT NARRATIVE The goals of this proposal are to develop and optimize compounds targeting apolipoproteinapoEinduced GABAergic interneuron impairment as a novel therapeutic approach for Alzheimer s disease and to test the efficacy of the lead GABAergic interneuron protectors in apoEknock in mice and human induced pluripotent stem cell derived neurons carrying the apoEallele!